7NB7

Structure of Mcl-1 complex with compound 6b

Summary for 7NB7

• Entry DOI: 10.2210/pdb7nb7/pdb
• Related: 6ybl 7nb4
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, (2~{R})-2-[[7-but-2-ynyl-5-(3-chloranyl-2-methyl-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid (3 entities in total)
• Functional Keywords: apoptosis, apoptosis-inhibitor complex, mcl-1, s64315, small molecule inhibitor, sbdd
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 79920.59

Authors

Dokurno, P.,Surgenor, A.E.,Kotschy, A. (deposition date: 2021-01-25, release date: 2021-10-13, Last modification date: 2024-01-31)

Primary citation

Sipos, S.,Balint, B.,Szabo, Z.B.,Ondi, L.,Csekei, M.,Szlavik, Z.,Proszenyak, A.,Murray, J.B.,Davidson, J.,Chen, I.,Dokurno, P.,Surgenor, A.E.,Pedder, C.,Hubbard, R.E.,Maragno, A.L.,Chanrion, M.,Colland, F.,Geneste, O.,Kotschy, A.
The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.
Acs Omega, 6:22073-22102, 2021

PubMed Abstract: Following the identification of thieno[2,3-]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable PD response. One compound was progressed into efficacy studies and inhibited tumor growth.

PubMed: 34497901
DOI: 10.1021/acsomega.1c02595

Experimental method

X-RAY DIFFRACTION (2.82 Å)