osi-027 and Neoplasms

Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to a family of atypical serine/threonine kinases in humans. They actively participate in a diverse set of cellular functions such as meiotic, V(D)J recombination, chromosome maintenance, DNA damage sensing and repair, cell cycle progression and arrest. ATR, ATM, DNA-PKcs, mTOR and hSMG are the members of the PIKK family that play an important role in in cancer cell proliferation, autophagy, and cell survival to radio and chemotherapy. Thereby targeting these PIKK kinases in cancer along with chemo/radiotherapy agents, can help in differential cytotoxicity towards cancer cell over the normal cell. In this review, we compile the various small molecule kinase inhibitors with respect to structural and strategic targeting of PIKK family members. Rapalogs, AZD8055, AZD2014, OSI-027, INK-128, MLN0128, VX970, NVP-BEZ235, Torin2, AZ20, and AZ31 are the diverse scaffolds which have successfully made into the pre-clinical trials either as mono or combinatorial therapy for the treatment of various human cancers. Their synthesis and pre-clinical trial highlight the challenges associated in the development process.

Topics: Benzamides; Benzoxazoles; Humans; Imidazoles; Molecular Targeted Therapy; Morpholines; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines; Signal Transduction; Triazines

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase, which regulates cellular metabolism and growth, and is a validated therapeutic target in various cancers. Recently, OSI-027, a selective ATP competitive inhibitor of mTOR, has been developed. The OSI-027 is an orally bioavailable compound whose anti-cancer activities were observed in various cancer cell lines and tumor xenograft models. The current study is the first attempt to explore the binding mode and the molecular-interactions of OSI-027 with mTOR using molecular docking and (un)binding simulation approaches. The study identified various interacting residues and their extent of involvement in binding was emphasized using different methods. The (un)binding simulation analyses provided snapshots of various phases in OSI-027 binding and identified residues important for binding but away from the catalytic site. Further, to explore a better binder for mTOR among OSI-027 analogs, the virtual screening led to propose an OSI-027 analog with CID: 73294902 as a better inhibitor than the OSI-027 and the native ligand PI-103. The binding mode of the proposed compound is compared with those of OSI-027 and other native inhibitors. The comparison of (un)binding simulation phases of proposed compound with that of OSI-027 revealed that both, bound to the same catalytic site, follow different (un)binding path. Thus, the current study presents computational insights into the OSI-027 mediated inhibition of mTOR kinase and proposed an OSI-027 analog as better mTOR inhibitor, and thus, a good drug for further research in experimental laboratories. J. Cell. Biochem. 118: 4558-4567, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Humans; Imidazoles; Molecular Docking Simulation; Neoplasm Proteins; Neoplasms; TOR Serine-Threonine Kinases; Triazines

The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted.. Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics.. One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients.. OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Imidazoles; Leukocytes, Mononuclear; Male; Maximum Tolerated Dose; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Middle Aged; Multiprotein Complexes; Neoplasms; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases; Triazines; Young Adult