9IB5

Structure of 18 (BI-2493) in complex with GDP-KRAS

Summary for 9IB5

• Entry DOI: 10.2210/pdb9ib5/pdb
• Related: 9IAP 9IAW 9IAY 9IB4
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: kras, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20303.90

Authors

Boettcher, J. (deposition date: 2025-02-11, release date: 2025-08-06, Last modification date: 2025-08-27)

Primary citation

Broker, J.,Waterson, A.G.,Hodges, T.R.,Abbott, J.R.,Arnold, A.,Bottcher, J.,Braun, N.,Cui, J.,Fuchs, J.E.,Gerstberger, T.,Gogg, S.,Hanner, S.,Herdeis, L.,Howell, L.W.,Mantoulidis, A.,Mayer, M.,Phan, J.,Rocchetti, F.,Sankar, K.,Sarkar, D.,Schaaf, O.,Sensintaffar, J.L.,Sun, Q.,Wunberg, T.,Fesik, S.W.
Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy.
J.Med.Chem., 68:15649-15668, 2025

PubMed Abstract: KRAS is one of the most highly validated cancer targets. Here we describe the design and synthesis of two reversible pan-KRAS inhibitors, BI-2865 and BI-2493. From our KRAS inhibitor program, we identified BI-2865, a potent noncovalent KRAS inhibitor that showed cellular activity against a broad spectrum of KRAS alleles and selectivity against HRAS and NRAS. Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.

PubMed: 40709733
DOI: 10.1021/acs.jmedchem.5c00576

Experimental method

X-RAY DIFFRACTION (1.011 Å)