molecules of the month


first-in-class allosteric SHP2 phosphatase inh.

oral agent in multiple trials for cancer

from 1.5M cmpd biochemical HTS + SBDD

J. Med. Chem., Sep. 24, 2020

Novartis, Cambridge, MA

Structure of TNO155
1 min read

TNO155 is an allosteric inhibitor of the SHP2 phosphatase, which has been a hot target in oncology recently due to its promotion of mutant KRAS activity as well as its potential role in cancer immune evasion. Phosphatases have been notoriously difficult to drug however, with reported phosphatase active site inhibitors typically having low potency, low selectivity, and poor properties due to the conserved, polar nature of the active site. Hence the Novartis team pursued allosteric inhibitors, and discovered a lead with a remarkable binding mode that stabilizes an inactive SHP2 conformation through interactions between three distinct protein domains. The primary amine in the molecule displaces a structural water and makes direct interactions with 3 different residues. TNO155 is the first allosteric…

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