Pan Phosphoinositide 3-kinase Inhibitor Research Articles

Abstract P3-11-01: An updated systematic review and meta-analysis of the safety and efficacy of phosphoinositide 3-kinase inhibitors (PI3Ki) in advanced breast cancer

Abstract Background In advanced breast cancer (ABC), the addition of pan-PI3Ki to the standard of care (SOC) treatment improves tumor response rate and progression free survival (PFS). Yet, further development of these drugs has been limited by their safety profile. Instead, selective PI3Ki were assessed and the Food and Drug Administration has recently approved the use of a selective PI3Ki based on a phase 3 randomized trial. Therefore, we updated our systematic review and meta-analysis to evaluate whether there is a difference in the efficacy and/or safety of pan versus selective PI3Ki in ABC. Methods The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant publications reporting randomized controlled trials between January 2000 and June 2019. Pooled hazard ratios (HR) for progression-free survival (PFS), and pooled odds ratios (OR) for objective response rate (ORR), disease control rate (DCR) and toxicity were computed and weighted using Mantel-Haenszel method and generic inverse variance. Subgroup analyses compared patients with and without PI3K pathway activation. Results Seven studies comprising 3,597 patients were included (5 studies with pan-PI3Ki and 2 studies with selective PI3Ki). Pan and selective PI3Ki decreased the risk of progression by 21% and 32% compared to SOC: HR: 0.79, 95%CI 0.0.71-0.88 and 0.68, 95%CI 0.57-0.81 respectively, p for test for subgroup differences: 0.16. An improvement in ORR was more pronounced with the use of selective versus pan PI3Ki: OR 2.67, 95%CI 1.78-4.00 and OR 1.31, 95%CI 1.01-1.71 respectively, p for test for subgroup differences: 0.004 and DCR was only improved with selective PI3Ki: OR 1.85 95%CI 1.37-2.51. A statistically significant increase in the toxicity of any grade and of grade 3 and higher was observed with pan and selective PI3Ki: 1) for any grade toxicity: OR 5.51, 95%CI 3.05-9.96, and OR 3.77, 95%CI 2.16-6.58 respectively, p for test for subgroup differences 0.16; 2) for grade 3 or higher toxicity: OR 1.91, 95%CI 1.76-2.08 and OR 2.41, 95%CI 2.07-2.82 respectively; p for test for subgroup difference 0.01. In subgroup analyses, the PFS improvement was more pronounced in the PI3K mutant subgroup: HR 0.72, 95%CI 0.63-81 for the PI3K mutant subgroup and HR 0.83, 95%CI 0.73-0.96 for the PI3K wild-type subgroup, p for test for subgroup differences 0.11. Conclusion While selective PI3Ki have a better effect on ORR, DCR and PFS in patients with ABC compared to pan PI3Ki; their toxicity profile is still clinically substantial. Rigorous safety monitoring and early medical intervention are needed to reduce treatment discontinuation, optimize efficacy and render these drugs more clinically usable. Citation Format: Jacques Raphael, Syed Hussaini, Kathleen I Pritchard, Prakesh Shah, Phillip Blanchette, Ricardo Fernandes, Danielle Desautels. An updated systematic review and meta-analysis of the safety and efficacy of phosphoinositide 3-kinase inhibitors (PI3Ki) in advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-01.

Benefits versus risk profile of buparlisib for the treatment of breast cancer

ABSTRACTIntroduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination.Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials.

Better Understanding of Phosphoinositide 3-Kinase (PI3K) Pathways in Vasculature: Towards Precision Therapy Targeting Angiogenesis and Tumor Blood Supply.

The intracellular PI3K-AKT-mTOR pathway is involved in regulation of numerous important cell processes including cell growth, differentiation, and metabolism. The PI3Kα isoform has received particular attention as a novel molecular target in gene therapy, since this isoform plays critical roles in tumor progression and tumor blood flow and angiogenesis. However, the role of PI3Kα and other class I isoforms, i.e. PI3Kβ, γ, δ, in the regulation of vascular tone and regional blood flow are largely unknown. We used novel isoform-specific PI3K inhibitors and mice deficient in both PI3Kγ and PI3Kδ (Pik3cg(-/-)/Pik3cd(-/-)) to define the putative contribution of PI3K isoform(s) to arterial vasoconstriction. Wire myography was used to measure isometric contractions of isolated murine mesenteric arterial rings. Phenylephrine-dependent contractions were inhibited by the pan PI3K inhibitors wortmannin (100nM) and LY294002 (10µM). These vasoconstrictions were also inhibited by the PI3Kα isoform inhibitors A66 (10µM) and PI-103 (1µM), but not by the PI3Kβ isoform inhibitor TGX 221 (100nM). Pik3cg(-/-)/Pik3cd(-/-)-arteries showed normal vasoconstriction. We conclude that PI3Kα is an important downstream element in vasoconstrictor GPCR signaling, which contributes to arterial vasocontraction via α1-adrenergic receptors. Our results highlight a regulatory role of PI3Kα in the cardiovascular system, which widens the spectrum of gene therapy approaches targeting PI3Kα in cancer cells and tumor angiogenesis and regional blood flow.

PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma.

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

The phosphoinositide 3-kinase signaling pathway is involved in the control of modified low-density lipoprotein uptake by human macrophages.

The transformation of macrophages into lipid-loaded foam cells is a critical early event in the pathogenesis of atherosclerosis. Both receptor-mediated uptake of modified LDL, mediated primarily by scavenger receptors-A (SR-A) and CD36 along with other proteins such as lipoprotein lipase (LPL), and macropinocytosis contribute to macrophage foam cell formation. The signaling pathways that are involved in the control of foam cell formation are not fully understood. In this study, we have investigated the role of phosphoinositide 3-kinase (PI3K) in relation to foam cell formation in human macrophages. The pan PI3K inhibitor LY294002 attenuated the uptake of modified LDL and macropinocytosis, as measured by Lucifer Yellow uptake, by human macrophages. In addition, the expression of SR-A, CD36 and LPL was attenuated by LY294002. The use of isoform-selective PI3K inhibitors showed that PI3K-β, -γ and -δ were all required for the expression of SR-A and CD36 whereas only PI3K-γ was necessary in the case of LPL. These studies reveal a pivotal role of PI3K in the control of macrophage foam cell formation and provide further evidence for their potential as therapeutic target against atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s11745-015-3993-0) contains supplementary material, which is available to authorized users.

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the α, -β, -γ, or -δ isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway.

Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

The pan-phosphoinositide 3-kinase (PI3K) inhibitor BKM120 was found, at high concentrations, to cause cell death in various cellular systems, irrespective of their level of PI3K addiction. Transcriptional and biochemical profiling studies were used to identify the origin of these unexpected and apparently PI3K-independent effects. At 5- to 10-fold, the concentration needed to half-maximally inhibit PI3K signaling. BKM120 treatment caused changes in expression of mitotic genes and the induction of a robust G(2)-M arrest. Tubulin polymerization assays and nuclear magnetic resonance-binding studies revealed that BKM120 inhibited microtubule dynamics upon direct binding to tubulin. To assess the contribution of this off-target activity vis-à-vis the antitumor activity of BKM120 in PI3K-dependent tumors, we used a mechanistic PI3K-α-dependent model. We observed that, in vivo, daily treatment of mice with doses of BKM120 up to 40 mg/kg led to tumor regressions with no increase in the mitotic index. Thus, strong antitumor activity can be achieved in PI3K-dependent models at exposures that are below those necessary to engage the off-target activity. In comparison, the clinical data indicate that it is unlikely that BKM120 will achieve exposures sufficient to significantly engage the off-target activity at tolerated doses and schedules. However, in preclinical settings, the consequences of the off-target activity start to manifest themselves at concentrations above 1 μmol/L in vitro and doses above 50 mg/kg in efficacy studies using subcutaneous tumor-bearing mice. Hence, careful concentration and dose range selection is required to ensure that any observation can be correctly attributed to BKM120 inhibition of PI3K.

Abstract 3741: Inhibition of PI3Kα kinase by a selective small molecule inhibitor suppresses B-cell proliferation and leukemic cell growth

Abstract Background: Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphotidylinositol. The PI3K pathway is frequently activated in human cancers and thus represents an attractive target for small molecule inhibitors. Pan-PI3K inhibitors currently in development have been associated with adverse side-effects such as insulin resistance, thus necessitating the need to develop isoform specific inhibitors of PI3K. Herein, we describe the biological and pharmacokinetic properties of RP5264, a small molecule PI3Kα inhibitors with scope to be further developed as a clinical candidate for hematological malignancies mediated by B-cells. Methods: Activity of RP5264 on individual PI3K isoforms was determined by a Homogenous Time Resolved Fluorescence assay (Millipore, Billerica, MA) with modifications. Cell based selectivity assays against β, α, or ≤ isoforms was assessed by testing the effect of the compound on PDGF, LPA, or c5a induced Akt phosphorylation in NIH-3T3 or RAW cells. Similarly, inhibition of cellular PI3Kα activity was determined in an IgM induced human B-cell proliferation as well as LPS-induced CD19 assays. Ability to arrest cell growth and induce apoptosis was also tested. Viability assays was conducted to determine the growth inhibitory effect of the compounds in leukemic cells. Pharmacokinetic behaviour of compounds in plasma after single dose oral administration was determined in female Balb/c mice. Results: RP5264 inhibited PI3Kα activity in enzyme and cell based assays with IC50 and EC50 values of 22.2 & 24.3 nM respectively. The compound displayed a high degree of selectivity over the alpha (>1000 fold), beta (>30-50 fold), and gamma (>15-50 fold) isoforms. Additionally, the compound caused a half-maximal inhibition of human whole blood CD19 cell proliferation between 100-300 nM. Treatment of PBMC with RP5264 resulted initially in a G2/M arrest followed by subsequent increase in the number of Sub G0 cells. Viability assays demonstrated that the compound caused a significant inhibition in growth as well as Akt phosphorylation of immortalized and primary leukemic cells. Further, the compound exhibited good oral absorption with favourable pharmacokinetic properties in rodents. Conclusions: Results demonstrate the PI3K delta selective nature of RP5264 along with an ability to suppress proliferation and Akt phosphorylation in cancer cells. In vitro selectivity and potency data indicate the therapeutics potential of the compounds in hematological cancers without the deleterious effects commonly associated with the Pan PI3K inhibitors. RP5264 is poised to enter clinical development in 2012. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3741. doi:1538-7445.AM2012-3741

Abstract 4489: Preclinical profile of novel, potent, and selective PI3K delta inhibitors

Abstract Background: Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphotidylinositol. The PI3K pathway is frequently activated in human cancers and thus represents an attractive target for small molecule inhibitors. Pan-PI3K inhibitors currently in development have been associated with adverse side-effects such as insulin resistance, thus necessitating the need to develop isoform specific inhibitors of PI3K. Herein, we describe the biological and pharmacokinetic properties of representative molecules from a series of novel and small molecule PI3KΔ inhibitors with scope to be further developed as clinical candidates for hematological malignancies such as acute myeloid leukemia and Non-Hodkin's lymphoma. Methods: Activity of test compounds on individual PI3K isoforms was determined by a Homogenous Time Resolved Fluorescence assay (Millipore, Billerica, MA) with modifications. Cell based selectivity assays against α, β, or γ isoforms was assessed by testing the effect of the compounds on PDGF, LPA, or c5a induced Akt phosphorylation in NIH-3T3 or RAW cells. Similarly, inhibition of cellular PI3KΔ activity was determined in a IgM induced human B-cell proliferation assay. Cell viability assay was conducted to determine the growth inhibitory effect of the compounds in cell lines representative of human acute and chronic leukaemia and lymphoma. Pharmacokinetic behaviour of compounds in plasma after single dose oral administration was determined in female Balb/c mice. Results: Among the compounds evaluated, RP5175 and RP5182 inhibited PI3KΔ activity in enzyme and cell based assays with IC50 values of 9.6 & 37.3 nM and EC50 values of 7.6 & 18.9 nM respectively. Besides, the compounds displayed a high degree of selectivity over the alpha (>500 fold), beta (>400 fold), and gamma (>15-40 fold) isoforms. Viability assays demonstrated that the compounds caused a significant inhibition in growth of THP-1, TOLEDO, and HL-60 cells. Pharmacokinetic studies in female Balb/c mice indicated good oral absorption with favourable peak plasma concentrations. Conclusions: Results demonstrate the PI3K delta selective nature of RP5175 and 5182 along with an ability to suppress proliferation of cancer cells. In vitro selectivity and potency data indicate the therapeutics potential of the compounds in hematological cancers without the deleterious effects commonly associated with the Pan PI3K inhibitors. The compounds are currently being tested for in vitro and in vivo efficacy across various cancer cell lines and xenograft models besides selectivity against other kinases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4489. doi:10.1158/1538-7445.AM2011-4489

Small Molecule SHIP Agonist AQX-MN100 Inhibits Multiple Myeloma (MM) Cell Growth In NOD/SCID Mice and Reduces Immune Suppressive Myeloid Derived Suppressor Cells (MDSC) and Regulatory T Cells (Tregs) In Mouse Model

AbstractAbstract 792We recently described a novel anti-MM drug (AQX-MN100) which is a small molecule agonist of SHIP (Src homology-2 (SH2) containing inositol-5¢-phosphatase) a signaling molecule found only in hemopoietic cells.(Ong et al, Blood; 110:1942, 2007) The molecule was developed using a high-throughput SHIP enzyme assay to screen an invertebrate marine natural product library and isolate the Pelorol.(Yang et al Org Lett; 7:1073, 2005) SHIP normally functions to negatively regulate the PI3K pathway important to normal hemopoietic cells growth and function. Inappropriate activation of the phosphoinositide 3- kinase (PI3K) pathway has been shown to be involved in the pathogenesis of MM and tumour aggressiveness correlates with the degree of activation. The critical role the PI3K/Akt signaling pathway plays in regulating MM cell survival, has stimulated efforts in designing therapeutics that target this pathway. Pan PI3K inhibitors have limited utility in a clinical setting because of their inhibitory effects on all isoforms of the PI3K family as well as non-PI3K targets. SHIP is an exceptionally good target for MM and other hematopoietic disorders that display elevated PI3K/Akt signaling because its expression is restricted to hemopoietic cells. We have shown that an analogue of Pelorol, AQX-MN100 is able to inhibit PI3K signaling and prevent phosphorylation of Akt. AQX-MN100 induced MM cell line apoptosis mediated by caspase and was specific for SHIP expressing cells which are exclusively hematopoietic. AQX-MN100 also enhances the growth inhibition effects of current myeloma drugs Dexamethasone and Bortezomib on human MM tumour cell lines in vitro. (Kennah et al Expt Hematol; 37:1274, 2009)In this study we have extended these finding to further evaluate the role of this compound in the treatment of myeloma. NOD-SCID mice were injected in the lateral flanks with 2 million luciferase tagged MM1.S multiple myeloma cells in Matrigel. Tumors were allowed to establish for two weeks and then either AQX-MN100 or vehicle was administered in an oil deposit subcutaneously in the lower flank at a dose of 50 mg/kg every three days. Tumor volume was quantified by imaging on a Xenogen IVIS 200 after 6 and 11 days. These studies demonstrate a significant reduction of tumor volume at 6 days p<0.05 and a highly significant reduction at 11 days p<0.01 in the mice receiving AQX-MN100 as compared to vehicle.We have shown that AQX-MN100 can directly kill MM cells in in vitro and in vivo. However, based on the known functions of SHIP, we predict that SHIP agonists will additionally target critical steps in MM pathogenesis in vivo, including the ability of MM cells to interact with stromal elements and to subvert the immune system. In order to evaluate this later feature we evaluated the ability of SHIP agonists to reverse the tumor associated immune suppression in MM patients. Tumor and host cell/tumor microenvironment secreted factors promote the production and activation of cells associated with cancer progression: the immune suppressive myeloid derived suppressor cells (MDSC) and regulatory T cells (Tregs). These cells normally regulate immune responses by inhibiting the activation of immune effector cells. The involvement of SHIP in the regulation of these cells is predicted by the observation that MDSC and Treg numbers are elevated in SHIP deficient mice. In this study Balb/C mice, 6 mice/group in duplicate were given either AQX-MN100 3 mg/kg and 10 mg/kg or vehicle once daily orally. At the end of three weeks mesenteric lymph nodes were harvested and subjected to FACS analysis to determine the proportion of MDSC (CD11b+Gr1+) and Treg (CD4+CD25+FoxP3+) cells. Spleen cells were also analysed for B cells, NK cells and granulocytes. In both of the AQX-MN100 treated groups the numbers of MDSC and Tregs were significantly lower than controls while Total CD11b, Total CD3, and spleen B, NK and granulocytes were not different from vehicle treated controls.The known role of SHIP in regulating hemopoietic cell function and the role of SHIP agonists in MM cell killing as well as additional actions on other aspects of MM pathophysiology may make them a powerful treatment option for MM, either alone or in synergy with other known MM therapies. Further development of this agent for the treatment of MM is ongoing. Disclosures:Mui:Aquinox: Equity Ownership, Patents & Royalties. Ong:Aquinox: Equity Ownership, Patents & Royalties. Anderson:Aquinox: Equity Ownership, Patents & Royalties. Sutherland:Celgene: Honoraria; Orthobiotech: Honoraria.

Phase 1 pharmacokinetic (PK) and pharmacodynamic(PD) evaluation of SF1126 a vascular targeted pan phosphoinositide 3- kinase (PI3K) inhibitor in patients with solid tumors

14532 Background: SF1126 is a conjugate of the well known pan PI3K inhibitor LY294002 with an RGD containing peptide designed for increased solubility and binding to specific integrins within the tumor compartment. This prodrug approach has been demonstrated to enhance delivery of the active inhibitor to the tumor resulting in increased antitumor efficacy coupled with improved tolerability in a number of preclinical studies including PC-3, DU-145, U87MG, U251MG, LN229, 786-O, MDA-MB-468 xenograft/orthotopic cancer models (Cancer Research, 2008;68(1)pp206–15). Methods: Patients are being dosed twice/ week by IV infusion over 1.5 hours in treatment cycles of 4 weeks. This is a dose escalation study with patients being entered onto a 3+3 modified Fibonacci schema. Activity of SF1126 is assessed by standard RECIST criteria, PD effects by 18F-deoxygluose PET scans 4 - 8 hours after dosing and at the end of cycle 1 and by enumeration of tumor cells. Results: To date 10 patients have been treated with SF1126 twice/ week for up to six months, the average treatment duration was 2 months (2 cycles). The dose escalation has progressed from 90 mg/m2 to 140 mg/m2 and to 180 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose and consisted of a hypersensitivity reaction manifested by hypotension and also diarrhea. In general the drug was well tolerated, 1 patient discontinued study because of an SAE, the remainder of the patients discontinued study for disease progression. The analysis of blood samples for parent drug (SF1126) and the hydrolysis product SF1101 (LY294002) showed a clearance and T1/2 values of CL: 178 ± 68 L/hr and T1/2 of 1.21 ± 0.58 hr respectively. Parent drug was measurable in some subjects at 5 and 15 min post-infusion, but not at any of the later sampling times. Intrapatient variability was low and subgroup of slow metabolizers is likely. Conclusions: SF1126 is well tolerated and converted in plasma rapidly to SF1101, which has a T1/2 of 1.2 ± 0.58 hrs. Dose escalation continues at 180 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Semafore Pharmaceuticals

A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity

PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (alpha v beta 3/alpha 5 beta 1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K inhibitory prodrugs for the treatment of cancer.

Class IA phosphoinositide 3-kinase isoforms and human tumorigenesis: implications for cancer drug discovery and development

The phosphoinositide 3-kinases are lipid kinases that are activated in response to external factors. They regulate a number of intracellular signaling pathways involved in cell motility, metabolism, survival, and growth. This review summarizes the current knowledge about specific contributions of Class IA phosphoinositide 3-kinases to tumorigenesis and presents a rationale for the development of isoform-specific inhibitors. In the last decade, the Class IA phosphoinositide 3-kinases have gained considerable attention as drug targets for the treatment of cancer. Indeed, pan-phosphoinositide 3-kinase inhibitors are being evaluated in early phases of clinical trials for the treatment of multiple human malignancies. Accumulating evidence suggests that selectively targeting individual isoforms is also possible. However, the patient population that is most likely to benefit from such selective compounds remains to be elucidated. Given the importance of the phosphoinositide 3-kinase pathway in the initiation and maintenance of human tumors, drugs that effectively target its constituents will be an invaluable addition to the arsenal of anticancer therapeutics. However, to fully capitalize on the central role of this pathway in malignancy, we must first fully understand the nuances of its multiple players.