University of California

D.e. Shaw Research, LLC

Relay Therapeutics, Inc.

Mary M Mader

Alexander M Taylor

Thomas H McLean

Fabrizio Giordanetto

Paul A Bartlett

Heike Schoenherr

Brandi M Hudson

Alessandro Boezio

Demetri T Moustakas

Pelin Ayaz

Ravi Kurukulasuriya

Dina A Sharon

Bakary-Barry Touré

The present disclosure relates to novel compounds of formula I-1, and pharmaceutical compositions thereof, and methods for inhibiting the activity of FGFR enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with FGFR signaling with the compounds and compositions of the disclosure.

FGFR inhibitors and methods of use thereof

Compounds are provided that are useful in inhibiting cysteine or serine proteinases. The compounds define a peptide backbone with a sulfur atom substituted in the backbone. A leaving group is associated, or bonded, to a carbon atom adjacent to the sulfur atom. The leaving group is displaceable either by hydrolysis under physiological conditions (with the hydrolyzed compound forming an aldehyde enzyme inhibitor) or by an active-site nucleophile of a cysteine or serine proteinase. When the leaving group is displaced by hydrolysis, then the compound functions as a protected derivative of the aldehyde functional group and is stabilized against oxidation or degradation, yet allows for release of the aldehyde moiety at the pharmacological site of action. The peptide sulfide analogues bearing a leaving group displaced by the active-site nucleophile covalently bond cysteine or serine proteinases and thus irreversibly inhibit these enzymes.

Cysteine proteinase inhibitors and inhibitor precursors

Growing community of inventors

Cambridge, MA, United States of America

Mary M Mader