Multi-target Anticancer Agents Research Articles

A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

Novel quinazolin-2-yl 1,2,3-triazole hybrids as promising multi-target anticancer agents: Design, synthesis, and molecular docking study

In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a, 14d, and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC50 0.103 µM) compared to Erlotinib (IC50 0.049 µM), good VEGFR-2 inhibitor (IC50 0.069 µM) compared to Sorafenib (IC50 0.031 µM), and stronger Topo II inhibitor (IC50 19.74 µM) compared to Etoposide (IC50 34.19 µM) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC50 31.02 µM and 56.3 µM) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.

The significance of quinazoline derivatives as potential multi-target anti-cancer agents: review article

The significance of quinazoline derivatives as potential multi-target anti-cancer agents: review article

A review on Millepachine and its derivatives as potential multitarget anticancer agents

Chalcones have a long history of being used for many medical purposes. These are the most prestigious scaffolds in medicine. The potential of Millepachine and its derivatives to treat various malignancies has been demonstrated in this review. The anticancer effects of Millepachine and its derivatives on ovarian cancer, hepatocellular carcinoma, breast, liver, colon, cervical, prostate, stomach, and gliomas are highlighted in the current review. Several genes that are crucial in reducing the severity of the disease have been altered by these substances. They mainly work by preventing tubulin polymerizing. They also exhibit apoptosis and cell cycle arrest at the G2/M phase. Additionally, these compounds inhibit invasion and migration and have antiproliferative effects. Preclinical studies have shown that Millepachine and its derivatives offer exceptional potential for treating a number of cancers. These results need to be confirmed in clinical research in order to develop viable cancer therapies.

Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics

Nitric oxide (NO) may be beneficial to overcoming drug resistance resulting from mutation of mTOR kinases and bypass mechanisms. In this study, a novel structural series of hybrids of mTOR inhibitor and NO donor were designed and synthesized via structure-based drug design (SBDD). Throughout the 20 target compounds, half of the compounds (13a, 13b, 19a-19d, 19f-19j) demonstrated attractive mTOR inhibitory activity with IC50 at single-digit nanomolar level. In particular, 19f exerted superior anti-proliferative activity against HepG2, MCF-7, HL-60 cells (HepG2, IC50 = 0.24 μM; MCF-7, IC50 = 0.88 μM; HL-60, IC50 = 0.02 μM) to that of the clinical investigated mTOR inhibitor MLN0128, and show mild cytotoxicity against normal cells with IC50 over 10 μM. 19a, with the most potent mTOR inhibitory activity in this series (IC50 = 3.31 nM), also displayed attractive cellular potency. In addition, 19f treatment in HL-60 reduces the levels of Phos-Akt and Phos-S6 in a dose-dependent manner, and releases NO in cells. In summary, 19f deserves further development as a novel mTOR-based multi-target anti-cancer agent.

Design, synthesis, molecular docking and biological evaluation of novel pyrazole derivatives bearing quinoxalinone moiety as multi-targeted anticancer agents

Based on a multitarget-directed drug design technique, a series of new quinoxalinone-based pyrazole derivatives (4a-h) were designed and synthesized. The potency of newly synthesized molecules to inhibit the antiproliferation of the human cancer cell lines MCF-7 (breast), HCT-116 (colon), and A549 (lung) was examined. The most effective compounds against the examined cancer cell lines were 4e, 4f, 4 g, and 4 h. Among these, compounds 4e and 4 h had a strong anticancer activity that was equivalent to sorafenib. The capacity of the potent compounds (4e, 4f, 4 g, and 4 h) to inhibit the in vitro activity of the thymidylate synthase (TS) enzyme, BRaf, and EGFR kinases was also tested. With IC50 values for the TS enzyme, BRaf kinase, and EGFR kinase ranging from 1.16 to 2.97 μM, 1.28 to 3.69 μM, and 1.93 to 4.28 μM, respectively, all the investigated compounds showed a noticeable inhibitory action. Among the synthesized hybrids, compound 4 h showed IC50 value of 2.04, 2.69 and 1.93 μM against MCF-7, HCT-116, and A549 cell line, respectively, and 1.16, 1.28 and 1.93 nM against TS, BRaf and EGFR kinase enzyme, respectively. All of the synthesized hybrids adhered to Lipinski's guidelines, which suggested that they would have favorable oral drug-like qualities. To determine the probable interaction between the potent compounds and the TS active site, molecular docking study was conducted.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3-Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB-510 showed an average diameter of 96 ± 3 nm, a zeta potential of -17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA-MB-468, SUM-149, MCF-7, and Ehrlich ascites carcinoma (EAC)as well as downregulation of phospho-AKT, phospho-ERK, and c-Myc levels. Importantly, bi-weekly treatment of Balb/c wild-type mice harboring EAC cells with HSB-510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.

Design, Synthesis and Biological Evaluation of Multi-Target Anti-Cancer Agent PYR26.

This study investigates the synthesis of a new compound, PYR26, and the multi-target mechanism of PYR26 inhibiting the proliferation of HepG2 human hepatocellular carcinoma cells. PYR26 significantly inhibits the growth of HepG2 cells (p < 0.0001) and this inhibition has a concentration effect. There was no significant change in ROS release from HepG2 cells after PYR26 treatment. The mRNA expressions of CDK4, c-Met and Bak genes in HepG2 cells were significantly inhibited (p < 0.05), while mRNA expression of pro-apoptotic factors such as caspase-3 and Cyt c was significantly increased (p < 0.01). The expression of PI3K, CDK4 and pERK proteins decreased. The expression level of caspase-3 protein was increased. PI3K is a kind of intracellular phosphatidylinositol kinase. PI3K signaling pathway is involved in signal transduction of a variety of growth factors, cytokines and extracellular matrix and plays an important role in preventing cell apoptosis, promoting cell survival and influencing cell glucose metabolism. CDK4 is a catalytic subunit of the protein kinase complex and is important for G1 phase progression of the cell cycle. PERK refers to phosphorylated activated ERK, which is translocated from cytoplasm to the nucleus after activation, and then participates in various biological reactions such as cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis and cell canceration. Compared with the model group and the positive control group, the tumor volume of the nude mice in the low-concentration PYR26 group, the medium-concentration group and the high-concentration group was smaller, and the organ volume was smaller than that in the model group and the positive control group. The tumor inhibition rates of low-concentration group PYR26, medium-concentration group and high-concentration group reached 50.46%, 80.66% and 74.59%, respectively. The results showed that PYR26 inhibited the proliferation of HepG2 cells and induced apoptosis of HepG2 cells by down-regulating c-Met, CDK4 and Bak, up-regulating the mRNA expression of caspase-3 and Cyt c genes, down-regulating PI3K, pERK and CDK4 proteins and up-regulating the protein level of caspase-3. In a certain range, with the increase in PYR26 concentration, the tumor growth was slower and the tumor volume was smaller. Preliminary results showed that PYR26 also had an inhibitory effect on the tumors of Hepa1-6 tumor-bearing mice. These results suggest that PYR26 has an inhibitory effect on the growth of liver cancer cells, therefore it has potential to be developed into a new anti-liver cancer drug.

Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 μM and 0.143 ± 0.008 μM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 μM and 0.067 ± 0.004 μM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.

Murine toxicology and pharmacokinetics of lead next generation galeterone analog, VNPP433-3β

VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Compound 2 is currently in development as potential new therapeutic for prostate and pancreatic cancers. The preliminary toxicity study reveals that the compound 2 was better tolerated by the normal male CD-1 mice than the male Nude mice. The maximum tolerated dose (MTD) in the Nude mice was estimated to be between 25 < 50 mg/kg. After oral dosing of compound 2 to male and female rats, the plasma concentration versus time curves were very consistent between animals and the AUClast increased with dose. Many plasmas concentration versus time curves profiles were nearly flat over 24 hr., suggesting extended absorption from the GI tract. Consequently, reliable values for half-life and AUCinf were not determined. Calculated oral bioavailability (using oral AUClast and excluding the outlier IV animal) ranged from 32 to 47 %. This should be considered a minimum value since the contribution to true AUC beyond 24 hr. is clearly not zero. Clearly, these toxicology and pharmacokinetics parameters pave the way for understanding the anticancer pharmacological actions and provide a meaningful basis for further preclinical development and eventual clinical development.

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach.

Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

Structure optimization, synthesis, and biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives as potential multi-targeted anticancer agents via Aurora A/ PI3K/BRD4 inhibition

Aurora A (Aurora kinase A), a critical regulator of cell mitosis, is frequently overexpressed in many malignant cancers, and has been considered as a promising drug target for cancer therapy. Likewise, Phosphatidylinositol 3-kinase alpha (PI3Kα) is also regarded as one of the most important targets in cancer therapy by mediating the cell growth and angiogenesis of various human cancers. In addition, Bromodomain-containing protein 4 (BRD4) modulates oncogene expressions of Myc, Aurora kinase and various RTKs. Recently, accumulating evidences indicated that hyperactivated or abnormally expressed Aurora A, PI3Kα or BRD4 are closely associated with drug resistance and poor prognosis of non-small cell lung cancer (NSCLC). Hence, simultaneous inhibition of Aurora A, PI3Kα, and BRD4 is expected to be a new strategy for NSCLC therapy. In this study, we performed further structure optimization of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H) -one based on previous study to obtain a series of derivatives for discovering potential Aurora A, PI3Kα and BRD4 multi-targeted inhibitors. MTT assay showed that most of the newly synthesized compounds exhibited an evident anticancer activity against the NSCLC cells. Among them, the IC50 values of the most potent compound 9a were 0.83, 0.26 and 1.02 μM against A549, HCC827 and H1975 cells, respectively. In addition, 9a markedly inhibited the Aurora A and PI3Kα kinase activities with IC50 values of 10.19 nM and 13.12 nM. Compound 9a induced G2/M phase arrests and apoptosis of HCC827 cells by simultaneous inhibition of Aurora A/PI3K/ BRD4 signaling pathways. Collectively, our studies suggested that 9a might be a potential multi-targeted inhibitor for NSCLC therapy.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Synthesis, biological evaluation and molecular docking studies of newly synthesized 4- amino quinazoline derivatives as potential multitarget anticancer agents.

Synthesis, biological evaluation and molecular docking studies of newly synthesized 4- amino quinazoline derivatives as potential multitarget anticancer agents.

Design, synthesis, and anticancer evaluation of N6 -hydrazone purine derivatives with potential antiplateletaggregation activity.

In our research on novel anticancer agents, a series of N6 -hydrazone purine derivatives were designed and synthesized by analysis of a pharmacophore model for ATP-competitive inhibitors. The activities screening results showed that N6 -hydrazone purine derivatives 21 and 26 not only showed potential antiproliferative activity against the A549 and MCF-7 cell lines comparable to Vandetanib as a positive control but also had moderate antiplatelet aggregation activity. In order to investigate the possible targets, a molecular docking study was carried out on the fourteen kinases associated with anticancer and antiplatelet aggregation activities. The results indicated that compounds 21 and 26 had the potential activity to target VEGFR-2, PI3Kα, EGFR, and HER2 kinases. The inhibition of the kinases assay showed that compound 26 could target VEGFR-2, PI3Kα, and EGFR (IC50 =0.822, 3.040 and 6.625 μM). All results indicated that compound 26 will be an encouraging framework as potential new multi-target anticancer agent with potential antiplatelet aggregation activity.

Metal complexes of benzimidazole-derived as potential anti-cancer agents: synthesis, characterization, combined experimental and computational studies.

In this study, a series of 14 Cu (II), Zn (II), Ni (II) and Ag (I) complexes containing bis-benzimidazole derivatives were successfully designed and synthesized from 2-(1H-benzimidazole-2-yl)-phenol derivatives and corresponding metal salt solutions. The compound structures were identified by FT-IR, 1H-NMR, powder X-ray diffraction and ESI-MS analyses, and the presence of the metal in the complexes was confirmed by ultraviolet-visible spectroscopy and ICP optical emission spectrometry. Electronic structure calculations were also carried out to describe the detailed structures in addition to the electronic absorption spectra of the ligands. The cytotoxic activity of the complexes was evaluated against three human cancer cell lines: lung (A549), breast (MDA-MB-231) and prostate (PC3) cancer cells. All complexes inhibited anti-proliferative cancer cells better than free ligands, especially Zn (II) and Ag (I) complexes, which are most sensitive to MDA-MB-231 cells. In addition, showing the growth inhibition of three cancer cell lines with IC50 < 10.4 µM, complexes C1, C3 and C14 could be considered potential multi-targeted anti-cancer agents.

Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species-mediated endoplasmic reticulum stress.

BackgroundPazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti‐SCLC mechanisms of pazopanib remain unclear.MethodsCell viability was evaluated by CCK‐8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic‐related molecules and ER‐stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH‐HA staining followed by flow cytometry. An NCI‐H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI‐H446 cell‐bearing NOD‐SCID mice.ResultsPazopanib dose‐ and time‐dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved‐caspase3 and Bax, and decreased Bcl‐2. Moreover, the PERK‐related ER‐stress pathway was potently activated by pazopanib treatment, inhibiting ER‐stress by salubrinal significantly reversing pazopanib‐mediated apoptosis in SCLC cell lines. Furthermore, pazopanib‐induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib‐induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI‐H446 xenograft growth and decreased Ki67 positive cells in the tumor.ConclusionOur findings indicate that pazopanib induces SCLC cell apoptosis through the ER‐stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.

Abstract 5406: Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Multiple studies have shown that progression of TNBC depends on more than one signalling pathways, suggesting that the therapies with multi-targeted anti-cancer agents will offer improved therapeutic benefit through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer and accordingly, improved delivery systems are needed. The present studies have investigated the encapsulation of PI3-Kδ/HDAC6 dual inhibitor into hybrid block co-polymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in TNBC cells. The prepared HSB-510 Quatramer nano-formulation showed an average diameter of 96 ±3 nm, the zeta potential of -17±2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a non-physiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of TNBC cell lines, MDA-MB-468, SUM-149 and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK and c-MYC levels. Importantly, bi-weekly treatment of BALB/c wild-type mice harbouring EAC cells (syngeneic mouse model) with HSB-510 at a dose of 25 mg/kg resulted in significant (76%) tumor growth inhibition (TGI). The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer nano-formulation of a novel PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for successful targeting of TNBC and potentially other cancer types. Citation Format: Sachchidanand Tiwari, Suiyang Liu, Mohammad Anees, Neha Mehrotra, Ashish Thakur, Gregory Tawa, Gurmit Grewal, Richard M. Stone, Surender M. Kharbanda, Harpal Singh. Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5406.

Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3β

VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Here, we describe a large multi-gram (92 g) scale synthesis of compound 2 starting from the commercially available dehydroepiandrosterone-3-acetate (DHEA, 6) via Galeterone (Gal, 1), in 8 steps with a 26% overall yield and 99.5% purity. The overall yield for the synthesis of Gal from DHEA improved from previously reported 47% to 59%. The advantages of this synthesis are as follows: (1) In the first two steps of Scheme 2, the change of solvents and reagents enabled the isolation of compounds 7 and 8 from heptane triturations, as column chromatography was eliminated in both steps. (2) In step 3 (deformylation) the catalyst required was reduced from 50% to 10% (wt/wt) of compound 8 which enable easy purification of compound 9, with modest increased yield. (3) The fourth step to produce Gal (1) was improved by using methanol, eliminating the use of tetrahydrofuran (THF) and dichloromethane, solvent which may be a problem as residual solvent contaminant. (4) In the final step 8, the imidazole-ring formation, inexpensive glyoxal (40% aqueous solution) was used in the reaction instead of expensive glyoxal trimer dihydrate. The structure of the target product (2, VNPP433-3β) was established by NMR spectroscopy, mass spectrometry and elemental analysis. Gal and VNPP433-3β exhibit more potent antiproliferative activities against CWR22Rv1 human prostate cancer cells compared to clinical drugs, Abiraterone and Enzalutamide.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation.

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.