Tuesday, May 26, 2015

Drugs in Clinical Pipeline: AZD3147

AZD3147 [(S)-1-(4-(4-(1-(cyclopropylsulfonyl)cyclopropyl)-6-(3-methylmorpholino) pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)thiourea] is an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 (IC50 mTOR = 0.0015 uM).

AZD3147 has a high degree of selectivity over the PI3K isoforms (PI3K-α,β,δ,γ IC50 = 0.92, 5.5, 9.4, 6.3 uM) and against a general panel of kinases (only 2 hits with greater than 50% inhibition when tested at 10 µM against a panel of 98 kinases). AZD3147 inhibits both mTORC1 and mTORC2 substrates in cells (IC50 mTOR = 0.006 uM), does not appear to inhibit CYP enzymes when tested at concentrations up to 10 µM, and shows no activity against the hERG (human ether-a-go-go-related gene) ion channel (IC50 greater than 100 µM).

Astrazeneca discovered AZD3147 using SAR studies on urea derivatives. Bioavailability of AZD3147 together with its encouraging physicochemical properties resulted in the selection of this compound for preclinical development [1].

Common Name: AZD3147
Synonyms:  AZD3147; AZD-3147; AZD 3147
IUPAC Name: (S)-1-(4-(4-(1-(cyclopropylsulfonyl)cyclopropyl)-6-(3-methylmorpholino) pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)thiourea
CAS Number: 1101810-02-9
Mechanism of Action: Kinase Inhibitor; mTOR Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: AstraZeneca

The mammalian target of rapamycin (mTOR), a serine/theronine kinase of approximately 289 kDa in size, is a member of the evolutionary conserved eukaryotic PI3K-related kinase (PIKK) family of atypical protein kinases which also include the protein kinases DNA-PK (DNA dependent protein kinase), ATM (ataxia-telangiectasia mutated) and ATR (ataxiatelangiectasia and Rad3 related). mTOR is a key target in the development of antitumor therapies. Activated by growth factor/mitogenic stimulation activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, mTOR is a central regulator of cell growth and proliferation. This PI3K-Akt-mTOR pathway is one of the most frequently dysregulated pathways in cancer [1].

1. Pike, K. G.; et. al. Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2. J Med Chem 2015, 58(5), 2326–2349.