Authors
Christine E Carbone, Heike Schönherr, Victor Y Zhao, Levi Pierce, Jing He, Kelley C Shortsleeves, Sandor Babik, Philip A Venter, Elaine B Krueger, Pascal D Fortin, Jeremy D Wilbur, Michael J Holliday
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 33. Pages e2529603123. Aug 18, 2026. Epub Aug 12, 2026.
Abstract
Genetic depletion of ARID1B has been shown to act in a synthetically lethal manner to selectively kill cancer cells with mutations in the tumor suppressor ARID1A, one of the most frequently altered proteins in human cancer. However, no precision therapeutic targeting ARID1B in ARID1A-mutant cancer has been developed due to the lack of a classically druggable small-molecule binding pocket on ARID1B. Here, we carried out molecular dynamics simulations on the small, globular AT-rich Interaction Domain (ARID) DNA-binding domain of ARID1B, demonstrating that the ARID exhibits significant conformational dynamics that expose a potentially ligandable site on the small domain. 2D protein-detected NMR fragment screening then allowed us to identify two compounds that bind to the ARID1B ARID with slow kinetics, suggestive of binding to a low-population conformation of the protein. X-ray structures of the ARID1B ARID bound to the compounds or close analogues demonstrated that they bind to two distinct cryptic pockets in the protein, exposed through different conformational rearrangements that reveal druggable sites absent in the ground state of the protein. Despite the high sequence homology between the ARID1A and ARID1B ARIDs, both cryptic pockets support selective binding to ARID1B, in one case greater than 140-fold, providing an avenue toward selectively targeting ARID1B in ARID1A-mutant cancer.
PMID:
42585010
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.
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