7NB4
Structure of Mcl-1 complex with compound 1
Summary for 7NB4
| Entry DOI | 10.2210/pdb7nb4/pdb |
| Related | 6ybl |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, (2~{R})-2-[[5-(3-chloranyl-2-methyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid, MAGNESIUM ION, ... (5 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 | 1 |
| Total formula weight | 20235.76 |
| 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 Cited by 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: 34497901DOI: 10.1021/acsomega.1c02595 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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