8E1A

Structure-based study to overcome cross-reactivity of novel androgen receptor inhibitors

Replaces:  4U4K

Summary for 8E1A

• Entry DOI: 10.2210/pdb8e1a/pdb
• Descriptor: Androgen receptor, 4-[4-(3-fluoro-2-methoxyphenyl)-1,3-thiazol-2-yl]morpholine, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: androgen receptor, agonist, antagonist, hormone receptor, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32684.09

Authors

Lallous, N.,Li, H.,Radaeva, M.,Dalal, K.,Leblanc, E.,Ban, F.,Ciesielski, F.,Chow, B.,Morin, M.,Singh, K.,Rennie, P.S.,Cherkasov, A. (deposition date: 2022-08-10, release date: 2022-09-14, Last modification date: 2024-04-03)

Primary citation

Radaeva, M.,Li, H.,LeBlanc, E.,Dalal, K.,Ban, F.,Ciesielski, F.,Chow, B.,Morin, H.,Awrey, S.,Singh, K.,Rennie, P.S.,Lallous, N.,Cherkasov, A.
Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors.
Cells, 11:-, 2022

PubMed Abstract: The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.

PubMed: 36139361
DOI: 10.3390/cells11182785

Experimental method

X-RAY DIFFRACTION (1.2 Å)