molecules of the month


brain-penetrant KRASG12C inhibitor

initial discovery for KRASG12C-positive tumors

from structure-based drug design

J. Med. Chem., July 3, 2023

AstraZeneca, Cambridge, UK

MOTM #3 - AZD4747
7 mins read

A CNS-Penetrant KRASG12C Inhibitor Intended for CNS-Metastatic Cancers AZD4747 is a CNS-penetrant, oral KRASG12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability (MW < 360 Da, cLogD < 2, TPSA < 90 Å2). AZD4747 is much smaller than marketed KRASG12C inhibitors but maintains exceptional cellular potency. Unlike adagrasib, AZD4747 does not have a basic amine, has a low PSA and a low MDCK efflux ratio, and can therefore achieve brain penetration without relying on other mechanisms, such as the P-gp inhibition speculated by Mirati. The team also encountered an unexpected toxicity that scientists working on covalents should pay…

request a trial

You don’t have time to read everything, but you can’t afford to fall behind.

Drug Hunter Premium is drug discovery, distilled, so you can quickly catch up and make informed decisions based on industry examples.

Get ahead now by requesting a trial.

already a member? log in: