9IGE

Structure of human Bcl-xL in complex with small molecule inhibitor

This is a non-PDB format compatible entry.

Summary for 9IGE

• Entry DOI: 10.2210/pdb9ige/pdb
• Related: 9i9e 9IGB 9IGC 9IGD
• Descriptor: Apoptosis regulator Bcl-2,Bcl-2-like protein 1, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-pyrrolo[2,3-c]pyridazin-7-yl]-1,3-thiazole-4-carboxylic acid, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: apoptosis, b-cell lyphoma, bcl-xl, drug design
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 37292.07

Authors

Dokurno, P.,Novak, T.,Kotschy, A.,Hubbard, R.E.,Davidson, J.,Murray, J. (deposition date: 2025-02-19, release date: 2026-06-24, Last modification date: 2026-07-08)

Primary citation

Timari, M.P.,Paczal, A.,Herner, A.,Molnar, M.,Madarasz, Z.,Nyerges, M.,Bedford, S.T.,Brooks, T.,Davidson, J.,Daniels, Z.,Dodsworth, M.,Dokurno, P.,Murray, J.B.,Parsons, R.,Sanders, E.,Smith, J.,Webb, P.,Whitehead, N.,Hubbard, R.E.,Starck, J.B.,Maragno, A.L.,Le Toumelin-Braizat, G.,Bresson, L.,Rocchetti, F.,Demarles, D.,Colland, F.,Geneste, O.,Kotschy, A.,Novak, T.
Structure-Based Discovery of Potent BCL-XL Inhibitors through Rescaffolding.
J.Med.Chem., 69:14804-14818, 2026

PubMed Abstract: Evasion of apoptosis is a hallmark of cancer. Deregulation of BCL-XL, a member of the BCL-2 family of proteins, has been linked to the development of various tumor types. This study presents the design and synthesis of BCL-XL inhibitors with novel mono- and bicyclic cores. The new structural features were optimized to combine high binding efficiency with the opening of diverse novel vectors for additional modifications. The lead compounds exhibited picomolar affinities and significant cellular potency in the BCL-XL-dependent MOLT-4 cell line, which also translated into marked tumor growth inhibition in a xenograft study. These findings highlight the potential of BCL-XL inhibitors as therapeutic agents in cancer treatment by targeting the apoptotic intrinsic pathway.

PubMed: 42283755
DOI: 10.1021/acs.jmedchem.6c00865

Experimental method

X-RAY DIFFRACTION (1.8 Å)