8T6F
Crystal structure of human MBP-Myeloid cell leukemia 1 (Mcl-1) in complex with BRD810 inhibitor
Summary for 8T6F
| Entry DOI | 10.2210/pdb8t6f/pdb |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein/Induced myeloid leukemia cell differentiation protein Mcl-1 Chimera, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | inhibitor, mcl1, mbp-fusion, brd810, apoptosis |
| Biological source | Escherichia coli K-12 More |
| Total number of polymer chains | 1 |
| Total formula weight | 58609.03 |
| Authors | Poncet-Montange, G.,Lemke, C.T. (deposition date: 2023-06-15, release date: 2024-06-19, Last modification date: 2024-11-06) |
| Primary citation | Rauh, U.,Wei, G.,Serrano-Wu, M.,Kosmidis, G.,Kaulfuss, S.,Siegel, F.,Thede, K.,McFarland, J.,Lemke, C.T.,Werbeck, N.,Nowak-Reppel, K.,Pilari, S.,Menz, S.,Ocker, M.,Zhang, W.,Davis, K.,Poncet-Montange, G.,Roth, J.,Daniels, D.,Kaushik, V.K.,Hubbard, B.,Ziegelbauer, K.,Golub, T.R. BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models. Nat Cancer, 5:1479-1493, 2024 Cited by PubMed Abstract: The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials. PubMed: 39179926DOI: 10.1038/s43018-024-00814-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.56 Å) |
Structure validation
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