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
SMILES:S=C(NCCO)NC1=CC=C(C2=NC(N3[C@@H](C)COCC3)=CC(C4(S(=O)(C5CC5)=O)CC4)=N2)C=C1
Mechanism of Action: Kinase Inhibitor; mTOR Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: AstraZeneca
References:
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.
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].
References:
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.
