9E30

Discovery of Potent, Highly Selective and Efficacious SMARCA2 Degraders - Compound 13

This is a non-PDB format compatible entry.

Summary for 9E30

• Entry DOI: 10.2210/pdb9e30/pdb
• Descriptor: Isoform Short of Probable global transcription activator SNF2L2, (12'S)-4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one, ZINC ION, ... (5 entities in total)
• Functional Keywords: protein degrader, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 44781.19

Authors

Strickland, C.,Rice, C. (deposition date: 2024-10-23, release date: 2024-12-18)

Primary citation

Li, Z.,Harikrishnan, L.S.,Xu, G.,Samanta, D.,Clemente, J.C.,Leng, L.,Tu, W.,Yang, L.,Huang, L.,Wang, M.,Wang, S.,Deng, Q.,Behshad, E.,Nagilla, R.,Orth, P.,Rice, C.,Strickland, C.,Mohammad, H.P.,Priestley, E.S.,Sui, Z.
Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.
J.Med.Chem., 2024

PubMed Abstract: We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines. We further highlight the optimization of the pharmacokinetic profile of a subset of compounds leading to potent and selective degradation of SMARCA2 in the xenograft model. These compounds provide valuable tools with desirable properties for continued exploration of the biology defining the susceptibility of SMARCA4 mutant cancers to selective loss of SMARCA2.

PubMed: 39570797
DOI: 10.1021/acs.jmedchem.4c01878

Experimental method

X-RAY DIFFRACTION (1.71 Å)