BI-2852 is a KRAS inhibitor for the switch I/II pocket (SI/II-pocket) by structure-based agent design with nanomolar affinity. BI-2852 is mechanistically distinct from covalent KRASG12C inhibitor (binds to switch II pocket) and binds ten-fold more strongly to active KRASG12D versus KRASwt (740 nM vs 7.5 μM). BI-2852 blocks GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in KRAS mutant cells.
BI-2852 is a switch SI/II pocket KRAS inhibitor with nanomolar affinity through structure-based drug design. It is mechanistically distinct from covalent KRASG12C inhibitors (binding switch II), binding to active KRASG12D 10-fold more strongly than KRAS wt (740 nM vs 7.5 μM). BI-2852 blocks GEF, GAP and effector interactions with KRAS, resulting in inhibition of downstream signaling and antiproliferative effects in KRAS mutant cells.
BI-2852 (Compound 1) (10 nM-10 μM; 2 hours) shows a dose-dependent pERK modulation and antiproliferative effect at EC 50 s of 5.8 μM and 6.7 μM in soft agar and low serum conditions in NCI-H358 cells.
| KRAS(G12C) 450 nM (IC 50 ) | KRAS(G12C) < p> 750 nM (Kd) |
KRAS(G12C): 450 nM (IC50); KRAS(G12C): 750 nM (Kd)
[1] Kessler D, et al. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci U S A. 2019 Aug 6; 116(32):15823-15829. DOI:
10.1073/pnas.1904529116[2] Dirk Kessler, et al. Drugging all RAS isoforms with one pocket. FUTURE MEDICINAL CHEMISTRY
