Inhibition Of Microtubule Polymerization Research Articles

New Indole-based Phenylthiazolyl-2,4-dihydropyrazolones as Tubulin polymerization inhibitors: Multicomponent synthesis, cytotoxicity evaluation, and in silico studies.

A facile multicomponent synthesis of new indole-based phenylthiazolyl-dihydropyrazolone hybrids, their structural characterization, biological evaluation, and in silico investigations as anticancer agents are reported. Lead molecule 5i of the series showed potent activity against MCF-7 breast cancer cells with an IC50 of 3.92± 0.01µM while showing minimal toxicity to normal human lung cells (IC50 = 69.85 ± 3.95 µM). Further studies show that the compound exhibits antiproliferative activity by inducing apoptosis in MCF-7 cancer cells. The wound healing assay indicated impaired cell migration under the concentration-dependent dosage. The lead molecule 5i also successfully inhibited the tubulin polymerase enzyme with an IC50 of 4.16 ± 0.18 µM. A flow cytometric assay indicated compound 5i induced apoptosis through G0 phase cell cycle arrest. The binding mode and interactions of the compound with the tubulin were predicted by molecular modelling and calculating binding free energies. These findings explain the current series as a new class of microtubule polymerization inhibitors with anticancer activity suitable for developing anticancer agents targeting tubulin.

Discovery of novel quinazoline derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potential anti-colon cancer effects

Tubulin is a critical target for cancer therapy, with colchicine binding site inhibitors (CBSIs) being the most extensively researched. A series of quinazoline derivatives designed to target the colchicine binding site of tubulin were synthesized and evaluated for their biological activities. The antiproliferative effects of these compounds were tested against six human cancer cell lines, and compound Q19 demonstrated potent antiproliferative activity against the HT-29 cell line, with an IC50 value of 51 nM. Additionally, further investigation revealed that Q19 effectively inhibited microtubule polymerization by binding to the colchicine binding site on tubulin. Furthermore, compound Q19 arrested the HT-29 cell cycle at the G2/M phase, induced apoptosis in these cells, and disrupted angiogenesis. Finally, compound Q19 exhibited potent inhibitory effects on tumor growth in HT-29 xenografted mice while demonstrating minimal toxic side effects and acceptable pharmacokinetic properties. These findings suggested that Q19 hold promise as a potential candidate for colon cancer therapy targeting tubulin.

Tirbanibulin as a Novel Treatment in Actinic Keratosis: A Literature Review

Introduction and purpose: Actinic keratosis (AK) is a common dermatological condition that primarily affects fair-skinned individuals due to cumulative ultraviolet light exposure, potentially leading to squamous cell carcinoma (SCC). AK therapy is divided into two main branches: lesion-directed therapy (cryotherapy, lasers, and surgical methods) and field cancerization-directed therapy (photodynamic therapy and topical agents). Unfortunately, the occurrence of local skin reactions (LSRs) and the therapy duration counted in weeks disrupt patient compliance. This study aims to review the clinical trials concerning the efficacy, safety, and adverse effects of tirbanibulin, a novel promising treatment for AK, which led to its approval and therapeutic development. Materials and methods: Literature available in PubMed and GoogleScholar databases were reviewed using the following keywords: actinic keratosis; actinic keratosis treatment; tirbanibulin. Results: Tirbanibulin's mechanism involves inducing apoptosis by inhibiting microtubule polymerization, which distinguishes it from other treatments that often cause significant inflammation. Clinical trials demonstrate its high efficacy in clearing AK lesions with a favorable safety profile, leading to regulatory approval. The ease of use and short therapy duration (5 days) ensure patient compliance and satisfaction with the treatment. Conclusion: Further longitudinal studies are necessary to confirm the long-term benefits and positioning of tirbanibulin in AK therapy. Raising public awareness about AK and the importance of early treatment with effective options like tirbanibulin is crucial for improving public health outcomes.

Ocular adverse events associated with antibody-drug conjugates in oncology: a pharmacovigilance study based on FDA adverse event reporting system (FAERS).

Antibody-drug conjugates (ADCs) have emerged as the focus and hotspots in the cancer field, yet the accompanying ocular toxicity has often been underestimated. We aimed to comprehensively and comparatively analyze the risk of ocular toxicity associated with various ADCs using the FDA Adverse Event Reporting System (FAERS) database. Data were extracted from the FAERS database from Q3 2011 to Q3 2023. We analyzed the clinical characteristics of ADCs-related ocular adverse events (AEs). These data were further mined by proportional analysis and Bayesian approach to detect signals of ADCs-induced ocular AEs. Moreover, the time to onset of ocular toxicity was also evaluated. A total of 1,246 cases of ocular AEs were attributed to ADCs. Ocular toxicity signals were observed in patients treated with belantamab mafodotin, brentuximab vedotin, enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan, trastuzumab deruxtecan, and trastuzumab emtansine. Of these, belantamab mafodotin, trastuzumab emtansine, and mirvetuximab soravtansine, whose payloads are microtubule polymerization inhibitors, were more susceptible to ocular toxicity. The ten most common ADCs-related ocular AEs signals are keratopathy [ROR = 1,273.52, 95% CI (1,129.26-1,436.21)], visual acuity reduced [ROR = 22.83, 95% CI (21.2-24.58)], dry eye [ROR = 9.69, 95% CI (8.81-10.66)], night blindness [ROR = 259.87, 95% CI (228.23-295.89)], vision blurred [ROR = 1.78, 95% CI (1.57-2.02)], photophobia [ROR = 10.45, 95% CI (9.07-12.05)], foreign body sensation in eyes [ROR = 23.35, 95% CI (19.88-27.42)], ocular toxicity [ROR = 144.62, 95% CI (117.3-178.32)], punctate keratitis [ROR = 126.21, 95% CI (101.66-156.69)], eye disorder [ROR = 2.71, 95% CI (2.21-3.32)]. In terms of onset time, sacituzumab govitecan displayed an earlier onset of 21days, while trastuzumab deruxtecan exhibited the latest onset of 223days. ADCs may increase the risk of ocular toxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADCs, combining the FAERS data with other data sources is crucial for monitoring the ocular toxicity of ADCs. In addition, novel ocular toxicity signals not documented in product labeling were detected. Further research will be necessary to validate our findings in the future.

Abstract Or101: Phospho-Mimic Mutation in Beta Tubulin Suppresses Arrhythmias and Improves Cardiac Connexin 43 Localization in Duchenne Muscular Dystrophy Mice

Duchenne Muscular Dystrophy (DMD) is a severe X-linked neuromuscular disorder, causing progressive muscle degeneration and premature death due to heart and skeletal muscle dysfunction. It is caused by mutations in the dmd gene, leading to the absence of dystrophin, a crucial protein for muscle integrity. There is no cure for DMD. Its associated dystrophic cardiomyopathy is the primary cause of mortality by age 20. Connexin-43 (Cx43) is a gap junction protein responsible for electrical signaling in the heart. Cx43 localizes at the intercalated disc of the cardiomyocyte (CM), forming an intercellular channel with adjacent CMs; In DMD, Cx43 hemichannel remodels to the lateral side of the cardiomyocyte. Our previous research indicated that phospho-mimic Cx43 carrying serine to glutamic acid substitutions at the triplet regulatory site S325, S328, S330 in mdx hearts suppressed Cx43 lateralization and improved cardiac rhythm. The phospho-mimic Cx43 also reduced pathological hyperdensity and transverse directionality of microtubules in mdx cardiomyocytes. Colchicine (Colch) treatment, known to inhibit microtubule polymerization, also improved cardiac rhythm and Cx43 localization in mdx mice. To phenocopy the effect observed with Colch, we generated a mouse model with a beta tubulin mutation at serine 172, which was replaced by glutamic acid (S172E). We found reduced arrhythmias and improved localization of Cx43 in mdx hearts carrying the S172E phospho-mimic mutant tubulin by electrocardiography and immunofluorescent staining, respectively. Moreover, the proteomics data showed that the level of phospho-Cx43 was also upregulated in mdx hearts with S172E tubulin mutation. Further investigation will explore how this mutation impacts protein regulation and electrophysiology, and elucidate its mechanism of action in microtubule polymerization. These studies investigate a regulatory link between microtubule dynamics and localization of Cx43, potentially suggesting a novel therapeutic target for DMD-associated cardiomyopathy.

Podophyllotoxin derivatives-tubulin complex reveals a potential binding site of tubulin polymerization inhibitors in α-tubulin adjacent to colchicine site

The colchicine site of β-tubulin has been proven to be essential binding sites of microtubule polymerization inhibitors. Recent studies implied that GTP pocket of α-tubulin adjacent to colchicine sites is a potential binding site for developing tubulin polymerization inhibitors. However, the structural basis for which type of structural fragments was more beneficial for enhancing the affinity of α-tubulin is still unclear. Here, podophyllotoxin derivatives-tubulin complex crystals indicated that heterocyclic with the highly electronegative and small steric hindrance was conducive to change configuration and enhance the affinity of the residues in GTP pocket of α-tubulin. Triazole with lone-pairs electrons and small steric hindrance exhibited the strongest affinity for enhancing affinity of podophyllotoxin derivatives by forming two hydrogen bonds with αT5 Ser178. Pyrimidine with the secondary strong affinity could bind Asn101 to make the αH7 configuration deflection, which reduces the stability of tubulin result in its depolymerization. Conversely, 4β-quinoline-podophyllotoxin with the weakest affinity did not interact with α-tubulin. The molecular dynamics simulation and protein thermal shift results showed that 4β-triazole-podophyllotoxin-tubulin was the most stable mainly due to two hydrogen bonds and the higher van der Waals force. This work provided a structural basis of the potential binding sites for extending the α/β-tubulin dual-binding sites inhibitors design strategy.

A methodology for specific disruption of microtubule polymerization into dendritic spines.

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes.

A phase 3 global study of telisotuzumab vedotin versus docetaxel in previously treated patients with c-Met 0verexpressing, EGFR wildtype, locally advanced/metastatic nonsquamous NSCLC (TeliMET NSCLC-01).

TPS8656 Background: Non-small cell lung cancer (NSCLC) encompasses over two-thirds of lung cancer diagnoses, most presenting as advanced disease. c-Met (MET protein) is overexpressed in NSCLC. In this study, we investigate telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate composed of a c-Met–targeting antibody (telisotuzumab) and a microtubule polymerization inhibitor (cytotoxin monomethyl auristatin E). Interim efficacy analysis of the Phase 2 LUMINOSITY study (NCT03539536) of Teliso-V monotherapy showed an objective response rate (ORR) of 37% (95% CI: 24–51) in previously treated patients (pts) with c-Met overexpressing epidermal growth factor receptor (EGFR) wildtype (WT) nonsquamous NSCLC and 52% (95% CI: 31–73) in the high c-Met overexpressing group (Camidge DR et al. J Clin Oncol. 2022;40(16_suppl):9016). Methods: This randomized, open-label, global Phase 3 study (NCT04928846) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of Teliso-V monotherapy compared with docetaxel in pts with locally advanced/metastatic c-Met overexpressing EGFR WT nonsquamous NSCLC who have progressed on prior therapy. Enrollment began in May 2022. To be eligible across global sites, pts must be ≥18 years old with c-Met overexpressing (ie, ≥25% tumor cells at 3+ intensity by IHC assay [anti-MET clone SP44; Roche Tissue Diagnostics]) locally advanced/metastatic EGFR WT NSCLC, with ECOG score ≤1. Pts must have progressed on at least one prior line of therapy, which can include no more than one line of prior chemotherapy, and must be naïve to c-Met–targeted antibodies and docetaxel. Target enrollment is 698 pts. Pts will be randomized 1:1 to Teliso-V (1.9 mg/kg every 2 weeks) and docetaxel (control, 75 mg/m2 every 3 weeks). Treatment continues until disease progression or discontinuation criteria are met. Co-primary endpoints are progression-free survival by independent central review and overall survival. Secondary endpoints include ORR, duration of response, and patient-reported outcomes. Safety, adverse events (AEs), drug discontinuation or dosing modification due to AEs, and tolerability will be assessed. Previously presented at the 2023 ESMO Congress, Final Publication Number: 1501TiP, Antonio Lugini et al. - Reused with permission. Clinical trial information: NCT04928846 .

Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: Primary analysis of the LUMINOSITY trial.

103 Background: Approximately 25% of patients (pts) with non-squamous (NSQ) EGFR wildtype (WT) NSCLC have c-Met protein overexpression (Ansell et al. 2022 CRUK), which is associated with a poor prognosis (Liang, Wang. Onco Targets Ther. 2020). Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the c-Met–overexpressing (OE) NSCLC population best suited to Teliso-V and expand selected group(s) for further evaluation of efficacy. We report on the primary analysis for pts with c-Met OE NSQ EGFRWT NSCLC. Methods: This phase 2, non-randomized, multicenter study enrolled pts with locally advanced/metastatic c-Met OE NSCLC, ≤2 prior lines of therapy (chemotherapy [CTx] + immunotherapy [IO] or sequential CTx + IO), and ≤1 line of chemotherapy. c-Met OE (Ventana MET [SP44] clinical trial assay [CTA]) was defined as ≥25% tumor cells with 3+ staining (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). Teliso-V was dosed at 1.9 mg/kg IV Q2W. Primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: 172 pts with NSQ EGFR WT NSCLC received ≥1 dose of Teliso-V and comprised the safety population; 161 (c-Met high, 78; c-Met int, 83) were included in baseline and efficacy analyses. Median age was 64 yrs (range 33–83), 69% were male, and 70% had ECOG PS 1. 97.5% had prior platinum and 82.0% had prior immune checkpoint inhibitor. Efficacy data are presented in Table below. ORR was 34.6% (c-Met high), 22.9% (c-Met int), 28.6% (overall). Median DOR was 9.0 mo (c-Met high), 7.2 mo (c-Met int), 8.3 mo (overall). Most common any-grade treatment-related AEs (TRAEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade 5 TRAEs occurred in 2 pts (interstitial lung disease, respiratory failure). Conclusions: Teliso-V has shown compelling and durable responses in pts with c-Met OE NSQ EGFR WT NSCLC, especially in pts with c-Met high. Teliso-V had an acceptable safety profile that was clinically manageable, which is consistent with previous data. Clinical trial information: NCT03539536 . [Table: see text]

Abstract PO3-25-10: Selective and Effective Targeting of Triple-Negative Breast Cancer by CMPD1: Inhibition of MAP kinase-activated protein kinase 2 and Microtubule Dynamics

Abstract Background: Microtubule-targeting agents (MTAs) have been widely utilized in cancer treatment, but the development of novel MTAs has faced limitations. CMPD1, a highly selective inhibitor of MAP kinase-activated protein kinase 2 (MK2) with dual functions as a microtubule inhibitor, shows promise as a targeted therapy for triple-negative breast cancer (TNBC). This study aimed to investigate the effects of CMPD1, targeting MK2 and acting as a microtubule inhibitor, on cell cycle progression, microtubule dynamics, and TNBC-related processes. Methods: CMPD1 was evaluated in non-transformed retinal pigment epithelial cells (RPE1) and TNBC cell lines, including MDA-MB-231 and MDA-MB-468 cells. Time-lapse microscopy and immunofluorescence staining were employed to observe the effects of CMPD1 on mitotic progression, cellular morphology, activation of the spindle assembly checkpoint (SAC), and microtubule dynamics. Anchorage-independent growth assays and in vivo studies using a TNBC xenograft model were performed to assess the impact of CMPD1 on colony formation, tumor growth, and metastasis. Results: CMPD1 treatment induced prometaphase arrest and mitotic slippage in both non-transformed and TNBC cells. This arrest was associated with SAC activation, evidenced by increased levels of Mad1 at kinetochores. CMPD1 exhibited robust microtubule depolymerization, primarily targeting microtubule plus-ends and inhibiting microtubule polymerization in vitro. Furthermore, CMPD1 disrupted the organization of the microtubule network in interphase cells and perturbed the mitotic spindle during mitosis. Additionally, CMPD1 treatment resulted in the formation of cytoplasmic protrusions, membrane deformations, and dynamic movement of clustered mitotic chromosomes. These morphological alterations were indicative of the impact of CMPD1 on cellular structures and processes during mitosis. Notably, CMPD1 demonstrated significant efficacy in inhibiting anchorage-independent growth in TNBC cells, highlighting its potential as an anti-TNBC agent. In the TNBC xenograft model, CMPD1 exhibited superior anti-tumor activity compared to the standard chemotherapeutic agent Taxol. Tumor growth was markedly suppressed, and the formation of metastatic lesions was significantly reduced upon CMPD1 treatment. Furthermore, CMPD1 treatment effectively inhibited TNBC cell migration and invasion, likely through its modulation of microtubule dynamics. The disruption of microtubule dynamics by CMPD1 impaired the ability of TNBC cells to migrate and invade surrounding tissues, which are crucial processes in cancer metastasis. Importantly, CMPD1 showed high selectivity for TNBC cells, exerting minimal cytotoxic effects on normal cells, and could be efficiently washed out. This selectivity and washout ability enhance its potential as a targeted therapeutic agent for TNBC treatment. Conclusions: CMPD1, a highly selective MK2 inhibitor and microtubule inhibitor, exerts profound effects on cell cycle progression, microtubule dynamics, and TNBC-related processes. It induces prometaphase arrest, mitotic slippage, and microtubule depolymerization, resulting in altered cellular morphology. CMPD1 displays high selectivity for TNBC cells, while sparing normal cells and allowing efficient washout, making it a promising therapeutic agent for TNBC treatment. Its inhibition of anchorage-independent growth, suppression of tumor growth in vivo, and ability to impair TNBC cell migration and invasion further underscore its potential as a targeted anti-TNBC therapy. Citation Format: Mamoru Takada, Yu-Chia Chen, Yu Muhan, Hideyuki Yamada, Junta Sakakibara, Hiroshi Fujimoto, Takeshi Nagashima, Masayuki Otsuka, Motoki Takaku, Aussie Suzuki. Selective and Effective Targeting of Triple-Negative Breast Cancer by CMPD1: Inhibition of MAP kinase-activated protein kinase 2 and Microtubule Dynamics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-10.

A pharmacovigilance study on antibody-drug conjugate (ADC)-related neurotoxicity based on the FDA adverse event reporting system (FAERS).

Background: Antibody-drug conjugates (ADCs) are a relatively new class of anticancer agents that use monoclonal antibodies to specifically recognize tumour cell surface antigens. However, off-target effects may lead to severe adverse events. This study evaluated the neurotoxicity of ADCs using the FDA Adverse Event Reporting System (FAERS) database. Research design and methods: Data were extracted from the FAERS database for 2004 Q1 to 2022 Q4. We analysed the clinical characteristics of ADC-related neurological adverse events (AEs). We used the reporting odds ratio (ROR) and proportional reporting ratio (PRR) for the disproportionality analysis to evaluate the potential association between AEs and ADCs. Results: A total of 562 cases of neurological AEs were attributed to ADCs. The median age was 65years old [(Min; Max) = 3; 92]. Neurotoxic signals were detected in patients receiving brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, and trastuzumab deruxtecan. The payloads of brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and trastuzumab emtansine were microtubule polymerization inhibitors, which are more likely to develop neurotoxicity. We also found that brentuximab vedotin- and gemtuzumab ozogamicin-related neurological AEs were more likely to result in serious outcomes. The eight most common ADC-related nervous system AE signals were peripheral neuropathy [ROR (95% CI) = 16.98 (14.94-19.30), PRR (95% CI) = 16.0 (14.21-18.09)], cerebral haemorrhage [ROR (95% CI) = 9.45 (7.01-12.73), PRR (95% CI) = 9.32 (6.95-12.50)], peripheral sensory neuropathy [ROR (95% CI) = 47.87 (33.13-69.19), PRR (95% CI) = 47.43 (32.93-68.30)], polyneuropathy [ROR (95% CI) = 26.01 (18.61-36.33), PRR (95% CI) = 25.75 (18.50-35.86)], encephalopathy [ROR (95% CI) = 5.16 (3.32-8.01), PRR (95% CI) = 5.14 (3.32-7.96)], progressive multifocal leukoencephalopathy [ROR (95% CI) = 22.67 (14.05-36.58), PRR (95% CI) = 22.52 (14.01-36.21)], taste disorder [ROR (95% CI) = 26.09 (15.92-42.76), PRR (95% CI) = 25.78 (15.83-42.00)], and guillain barrier syndrome [ROR (95% CI) = 17.844 (10.11-31.51), PRR (95% CI) = 17.79 (10.09-31.35)]. The mortality rate appeared to be relatively high concomitantly with AEs in the central nervous system. Conclusion: ADCs may increase the risk of neurotoxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADC drugs, combining the FAERS data with other data sources is crucial for monitoring the neurotoxicity of ADCs. Further studies on the potential mechanisms and preventive measures for ADC-related neurotoxicity are necessary.

SEPTIN10-mediated crosstalk between cytoskeletal networks controls mechanotransduction and oncogenic YAP/TAZ signaling

The transcriptional co-activators of the Hippo pathway, YAP and TAZ, are regulated by mechanotransduction, which depends on dynamic actin cytoskeleton remodeling. Here, we identified SEPTIN10 as a novel cytoskeletal protein, which is transcriptionally regulated by YAP/TAZ and whose overexpression correlates with poor survival and vascular invasion in hepatocellular carcinoma (HCC) patients. Functional characterization demonstrated that SEPTIN10 promotes YAP/TAZ-dependent cell viability, migration and invasion of liver cancer cells. Mechanistically, SEPTIN10 interacts with actin and microtubule filaments supporting actin stress fiber formation and intracellular tension through binding to CAPZA2 while concurrently inhibiting microtubule polymerization through the blockage of MAP4 function. This functional antagonism is important for cytoskeleton-dependent feedback activation of YAP/TAZ, as microtubule depolymerization induces actin stress fiber formation and subsequently YAP/TAZ activity. Importantly, the crosstalk between microfilaments and microtubules is mediated by SEPTIN10 as its loss abrogates actin stress fiber formation after microtubule disruption. Together, the YAP/TAZ target gene SEPTIN10 controls the dynamic interplay between actin and microtubule filaments, which feeds back on Hippo pathway activity in HCC cells and thus acts as molecular switch with impact on oncogenic signaling and cancer cell biology.

Novel dual action PARP and microtubule polymerization inhibitor AMXI-5001 powerfully inhibits growth of esophageal carcinoma both alone and in combination with radiotherapy

Novel dual action PARP and microtubule polymerization inhibitor AMXI-5001 powerfully inhibits growth of esophageal carcinoma both alone and in combination with radiotherapy

The discovery of water-soluble indazole derivatives as potent microtubule polymerization inhibitors

Taking a previously discovered indazole derivative 1 as a lead, systematic structural modifications were performed with an indazole core at the 1- and 6-positions to improve its aqueous solubility. Among the designed indazole derivatives, 6-methylpyridin-3-yl indazole derivative 8l and 1H-indol-4-yl indazole derivative 8m exhibited high potency in the low nanomolar range against A549, Huh-7, and T24 cancer cells, including Taxol-resistant variant cells (A549/Tax). As a hydrochloride salt, 8l exhibited much improved aqueous solubility, and its log P value fell into a favorable range. In mechanistic studies, 8l impeded tubulin polymerization through interacting with the colchicine site, resulting in cell cycle arrest and cellular apoptosis. In addition, compared to lead compound 1, 8l reduced cell migration and led to more potent inhibition of tumor growth in vivo without apparent toxicity. In summary, indazole derivative 8l could work as a potential anticancer agent and deserves further investigation for cancer therapy.

Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance.

Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50 values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 μM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.

Anti-tumor and cardiotoxic effects of microtubule polymerization inhibitors: The mechanisms and management strategies.

Microtubule polymerization inhibitors (MPIs) have long been used as anticancer agents because they inhibit mitosis. Microtubules are thought to play an important role in the migration of tumor cells and the formation of tumor blood vessels, and new MPIs are being developed. Many clinical trials of novel MPIs have been conducted in humans, while some clinical studies in dogs have also been reported. More attempts to apply MPIs not only in humans but also in the veterinary field are expected to be made in the future. Meanwhile, MPIs have a risk of cardiotoxicity. In this paper, we review findings on the pharmacological effects and cardiotoxicity of MPIs, as well as the mechanisms of their cardiotoxicity. Cardiotoxicity of MPIs involves not only the direct effects of MPIs on cardiomyocytes but also their effects on vascular function. For example, hypertension induced by impaired vascular function also contributes to the exacerbation of myocardial damage, and blood pressure control may be useful in reducing cardiotoxicity. By combined administration of MPIs and other anticancer agents, MPI efficacy may be enhanced, thereby potentially allowing to keep MPI dosage low. Measurement of myocardial injury markers in blood and echocardiography may be useful for monitoring cardiotoxicity. In particular, two-dimensional speckle tracking may have high sensitivity for the early detection of MPI-induced cardiac dysfunction. The exploration of the potential of new MPIs while understanding their toxicity and how to deal with them will lead to the further development of cancer chemotherapy.

DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)

Abstract BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.

Lactate: A critical regulator of cell proliferation via anaphase promoting complex remodeling

Lactate: A critical regulator of cell proliferation via anaphase promoting complex remodeling

Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC).

TPS9149 Background: Teliso-V is a first-in-class anti–c-Met antibody-drug conjugate composed of the monoclonal antibody telisotuzumab (ABT-700), a cleavable valine-citrulline (dipeptide) linker, and cytotoxic monomethylauristatin E (MMAE; potent microtubule polymerization inhibitor). Direct MMAE payload delivery to c-Met protein overexpressing (OE) cells enables Teliso-V to work independently of c-Met signaling. In NSCLC, while c-Met OE is more common than MET gene amplification (Amp), about 90% of MET Amp tumors will also be c-Met OE. In an ongoing phase 2 trial, Teliso-V showed encouraging efficacy and acceptable safety in previously treated c-Met OE NSQ NSCLC population (Camidge et al. JCO.2022.40.16_suppl.9016). From this study, a retrospective analysis of 10 patients with MET Amp (≥1.8 MET gene to chromosome 7 copy number ratio by fluorescence in situ hybridization [FISH]) demonstrated an objective response rate (ORR) of 80%. Described here is an ongoing phase 2 study evaluating efficacy and safety of Teliso-V monotherapy in patients with previously untreated MET Amp locally advanced/metastatic NSQ NSCLC. Methods: This is a phase 2, single-arm, open-label, global study (NCT05513703). Eligible patients (≥18 years) have histologically documented advanced/metastatic NSQ NSCLC, measurable disease by RECIST v1.1, confirmed MET Amp determined centrally by FISH or locally by FISH, tissue next-generation sequencing (NGS), or plasma NGS using sponsor-approved assays. Additional eligibility criteria include Eastern Cooperative Oncology Group performance status 0 or 1, no alterations in EGFR, ALK, ROS1, or BRAF that predict sensitivity to targeted therapy, no prior systemic therapy for locally advanced or metastatic NSCLC, no prior c-Met–targeted antibody therapy. Teliso-V is administered intravenously at 1.9 mg/kg every 2 weeks until disease progression, intolerable toxicity, or other study drug discontinuation criteria are met. Primary endpoint is ORR assessed by independent central review (ICR). Secondary endpoints include duration of response and disease control rate, progression-free survival per ICR, overall survival, patient-reported outcomes (PROs). Tumor assessments (per RECIST v1.1) are performed at baseline and approx. every 6 (year 1), 8 (year 2), and 12 weeks (year 3 and beyond). PROs are assessed through validated questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30, EQ-5D-5L). Safety and tolerability are evaluated by adverse events, physical examinations, laboratory data, and vital signs. Pharmacokinetic and biomarker evaluations may be used for exploratory analyses. The trial intends to enroll approx. 70 efficacy-evaluable patients, with interim analyses planned after 20 and 50 patients are able to be followed for ≥6 months. The study was open to enrollment as of Nov 2022. Clinical trial information: NCT05513703 .

Abstract CT214: Preliminary efficacy of telisotuzumab vedotin (Teliso-V) treatment in the 2L/3L setting in MET gene amplified (MET Amp), c-Met protein overexpressing (c-Met OE), non-squamous, non-small cell lung cancer (NSQ NSCLC): Retrospective analysis of LUMINOSITY

Abstract Background: Teliso-V is a first-in-class c-Met-directed antibody-drug conjugate comprising the monoclonal antibody telisotuzumab, a cleavable valine-citrulline linker, and the potent microtubule polymerization inhibitor monomethyl auristatin E. In a Phase 2 study (LUMINOSITY, NCT03539536), Teliso-V has shown an acceptable safety profile and encouraging efficacy in c-Met OE NSQ NSCLC. In NSCLC, while c-Met OE is more common than MET Amp, occurring in 25% of patients (pts) versus 1-5%, respectively, ~90% of MET Amp tumors are c-Met OE. We performed a retrospective analysis of LUMINOSITY to characterize the efficacy of Teliso-V in previously treated pts with MET Amp, c-Met OE NSQ NSCLC. Methods: Pts had locally advanced/metastatic NSQ NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, MET Amp by fluorescence in situ hybridization (FISH), and tumors that were c-Met OE by central immunohistochemistry (IHC). MET Amp was defined as a ratio of ≥1.8 MET gene copy number (GCN) to chromosome 7 (CEP7) CN by FISH with levels of amplification defined as high, ≥5; intermediate (int), >2.2 - <5; or low, ≥1.8 - ≤2.2. MET GCN by FISH was classified as high, ≥10; int, 5 - <10; or low, <5. c-Met OE was defined as ≥25% of tumor cells at 3+ intensity by IHC; patients were classified as MET IHC 3/25 (25 - 49% tumor cells at 3+) or MET IHC 3/50 (≥50% tumor cells at 3+). Teliso-V was dosed at 1.9 mg/kg IV Q2W. Results: As of 27 May 2021, 10 pts with MET Amp were treated with Teliso-V. The median age was 69 (48-75), 9 pts were male, 5 were White, 9 had a history of smoking (current or former), and 9 had an ECOG score of 0-1. The median MET/CEP7 ratio was 3.3 (1.84-12.17) with 4, 1, and 5 pts having high, int, and low levels of amplification, respectively. The median MET GCN was 10.98 (6.95-65.00) with 6, 3, and 1 pts having high, int, and low GCN, respectively. 7 pts were MET IHC 3/50 and 3 were MET IHC 3/25. Pts with MET Amp treated with Teliso-V monotherapy had an ORR of 80% (95% CI [44.4, 97.5]; n=8; all partial response) by independent central review, and a disease control rate of 90%. The median duration of response was 6.9 months. Among the 8 responders, 62.5% (n=5/8) are still event-free and being followed up for disease assessment. Teliso-V monotherapy resulted in median progression-free survival (PFS) of 8.0 months (95% CI [1.3, -]; n=10), compared with 5.7 months (95% CI [2.6, 9.8]) on the last prior line of systemic cancer therapy (n=10). Conclusions: Teliso-V demonstrated a promising ORR in previously treated pts with MET Amp NSQ NSCLC with c-Met OE and improved PFS when compared to last prior systemic cancer therapy. These preliminary data support the ongoing Phase 2 trial of Teliso-V monotherapy in pts with previously untreated MET Amp NSCLC (TeliMET NSCLC-02; NCT05513703), which is currently enrolling. Citation Format: D. Ross Camidge, Jonathan Goldman, Athan Vasilopoulos, Peter Ansell, Summer Xia, Ellen Bolotin, Jim Looman, Christine Ratajczak, Elysa Noon, Shun Lu. Preliminary efficacy of telisotuzumab vedotin (Teliso-V) treatment in the 2L/3L setting in MET gene amplified (MET Amp), c-Met protein overexpressing (c-Met OE), non-squamous, non-small cell lung cancer (NSQ NSCLC): Retrospective analysis of LUMINOSITY [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT214.