Big things come in little packages

A recent article by a team in Genentech highlighted a RIPK1 inhibitor clinical candidate with GDC-8264 with a Ki (app) value of 710 pM. This candidate was derived from the HTS hit (Compound 1), which had it’s own outstanding potency for an HTS hit of 84 nM.

The team screened a library of 2.7M compounds leading to the discovery of this series and clinical candidate. If we look at the “tale-of-the-tape” it comes in something like this..

Properties	Compound 1	GDC-8264	Delta
MW	285.12	271.11	-14.01
clogP	3.46	3.19	-0.27
HAC	18	20	+2
LE	0.55	0.79	+0.24
LLE	3.61	6.95	+3.34

This might be a record for the biggest change in potency with the smallest change in structure that I’ve seen.  With a mere +2 in HAC, the molecule dips into the pM range for potency.    A perfect ring-constrain (dare I say “microcycle?”) enabled by SBDD led to the breakthrough in the series.