8A31

p53 cancer mutant Y220C in complex with iodophenol-based small-molecule stabilizer JC694

Summary for 8A31

• Entry DOI: 10.2210/pdb8a31/pdb
• Descriptor: Cellular tumor antigen p53, 4-(3-fluoranylpyrrol-1-yl)-3,5-bis(iodanyl)-2-oxidanyl-benzoic acid, ZINC ION, ... (5 entities in total)
• Functional Keywords: tumor suppressor p53, cancer mutant, drug discovery, small-molecule stabilizer, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 50230.49

Authors

Balourdas, D.I.,Stephenson Clarke, J.R.,Baud, M.G.J.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2022-06-06, release date: 2022-11-30, Last modification date: 2024-01-31)

Primary citation

Stephenson Clarke, J.R.,Douglas, L.R.,Duriez, P.J.,Balourdas, D.I.,Joerger, A.C.,Khadiullina, R.,Bulatov, E.,Baud, M.G.J.
Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C.
Acs Pharmacol Transl Sci, 5:1169-1180, 2022

PubMed Abstract: The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer cases per annum and is one of the most prevalent p53 mutants overall. It harbors a narrow, mutationally induced pocket at the surface of the DNA-binding domain that destabilizes p53, leading to its rapid denaturation and aggregation. Here, we present the structure-guided development of high-affinity small molecules stabilizing p53-Y220C , along with the synthetic routes developed in the process, structure-activity relationship data, and confirmation of their binding mode by protein X-ray crystallography. We disclose two new chemical probes displaying sub-micromolar binding affinity , marking an important milestone since the discovery of the first small-molecule ligand of Y220C in 2008. New chemical probe JC744 displayed a = 320 nM, along with potent protein stabilization. This study, therefore, represents a significant advance toward high-affinity Y220C ligands for clinical evaluation.

PubMed: 36407959
DOI: 10.1021/acsptsci.2c00164

Experimental method

X-RAY DIFFRACTION (1.46 Å)