Wednesday, November 18, 2015

Drugs in Clinical Pipeline: Vistusertib | mTOR Inhibitors | Kinase Inhibitors

Vistusertib [3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide] is an oral, potent and selective dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. It is under clinical trials against various cancers as monotherapy as well in combination with other anti-cancer agents such as Estrogen Receptor Positive (ER+) Metastatic Breast Cancer, Metastatic Renal Cancer, Glioblastoma Multiforme, Ovarian Cancer etc [1, 2].
Vistusertib: 2D and 3D Structure

mTOR as Target for Cancer Treatment
Growth factor/mitogenic activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin associated protein), RAFTl (rapamycin and FKBP12 target 1), RAPTl (rapamycin target 1) - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)) [3]. 
mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases. The mTOR protein is a member of the PB-kinase like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PI3-kinase and the other family members, e.g. DNA-PKcs (DNA dependent protein kinase), ATM (Ataxia- telangiectasia mutated).
PI3K-Akt-mTOR pathway is one of the most frequently dysregulated pathways in cancer. The mammalian target of rapamycin (mTOR) is a key target in the development of antitumor therapies. The finding that mTOR can exist in an alternative, rapamycin insensitive, complex that signals to Akt opened up a new line of thinking for the researchers. The existence of both a rapamycin sensitive complex (mTORC1) and a rapamycin insensitive complex (mTORC2) may provide an explanation for the differences observed in the earlier research works. Rapamycin and its analogues have been shown to activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1. Moreover, this is associated with a shorter time to progression in glioblastoma patients treated with rapamycin suggesting that dual mTORC1 and 2 inhibitors that inhibit AKT signaling could offer greater clinical benefit compared with rapalogues. In addition, dual mTORC1 and mTORC2 inhibitors may exhibit a broader spectrum of clinical activity [2].

 Vistusertib as mTOR Inhibitor
Vistusertib is a potent inhibitor of mammalian target of rapamycin (mTOR) kinase (IC50 = 0.0028 uM) and displays a high level of selectivity against other members of the PIKK family (IC50 PI3Kα = 3.8 uM, PI3Kβ, γ, δ greater than 29 uM, respectively). It was inactive against a general panel of over 200 kinases when tested at 10 uM. In in vivo studies, Vistusertib has been shown to modulate downstream markers of mTORC1 (inhibition of pS6 at Ser235/236 IC50 = 0.2 uM) and mTORC2 (inhibition of pAKT at Ser473 IC50 = 0.08 uM). Moreover, it has shown dose-dependent tumor growth inhibition in a mouse MCF7 xenograft model alongside modulation of mTORC1 and mTORC2 biomarkers.
Vistusertib showed excellent aqueous solubility (more than 600 uM), margin to the hERG (IC50 = 47.5 uM) and was shown to have good oral exposure in both rat (100%) and mouse (40%). Vistusertib shows consistent exposure in rodents and a low turnover in human hepatocyte incubations and was subsequently selected for clinical development. Vistusertib is currently in Phase I/II [1, 2].
Dosages and Approvals:
Vistusertib (Tradename: -) is discovered and developed by Kudos Pharmaceuticals, later aquired by AstraZeneca. It is still under clinical trials.

Reported Activities for Vistusertib
IC50 (mTOR enzyme assay) = 2.8 nM
IC50 (PI3Kα enzyme assay) = 3.8 uM
IC50 (PI3Kβ enzyme assay) = greater than 30 uM
IC50 (PI3Kγ enzyme assay) = greater than 30 uM 
IC50 (PI3Kδ enzyme assay) = greater than 29 uM


Common name: AZD2014; AZD-2014; AZD 2014; Vistusertib
Trademarks: -
Molecular Formula: C25H30N6O3
CAS Registry Number: 1009298-59-2
CAS Name: 3-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide
Molecular Weight: 462.54
InChI: InChI=1S/C25H30N6O3/c1-16-14-33-11-9-30(16)23-20-7-8-21(18-5-4-6-19(13-18)24(32)26-3)27-22(20)28-25(29-23)31-10-12-34-15-17(31)2/h4-8,13,16-17H,9-12,14-15H2,1-3H3,(H,26,32)/t16-,17-/m0/s1
Mechanism of Action: Kinase Inhibitors; Dual mTOR Inhibitor
Activity: Various Cancers; Treatment for Breast Cancer; Anti-Cancer Agents
Status: Phase Trials (US)
Chemical Class: Small-molecules; Benzamides; Morpholines; Pyridines; Pyrimidines
Originator: AstraZeneca
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