molecules of the month

“compound 24”

>50x family-selective HPK1 kinase inhibitor

tumor clearance w/ PD-1i (oral 100 mpk BID)

from IRAK4 inhibitor and homology modeling

ACS. Med. Chem. Lett., Feb. 19, 2021

Bristol Myers Squibb, Cambridge, MA

1 min read

6. The Bristol Myers Squibb (BMS) HPK1 kinase inhibitor, “compound 24” is an oral tool compound intended for cancer immunotherapy, with >50x selectivity against family members including GLK. The starting point was an IRAK4 kinase inhibitor identified from historical kinome selectivity data. A homology-model based on MST1 was used for optimization. Interestingly this uncharged kinase inhibitor possesses a cyclic lactone which binds to a backbone N-H in a co-crystal structure without hydrolizing and a primary alcohol which binds to a front-pocket aspartate. Oral BID dosing (100 mg/kg) in combination with an anti-PD-1 antibody led to a 100% cure rate in a syngeneic tumor model.

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