Summary for 9PQ7
| Entry DOI | 10.2210/pdb9pq7/pdb |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, 17-chloranyl-33-fluoranyl-12-[2-(2-methoxyethoxy)ethyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,12,13,24-pentazaheptacyclo[27.7.1.1^{4,7}.0^{11,15}.0^{16,21}.0^{20,24}.0^{30,35}]octatriaconta-1(36),4(38),6,11(15),13,16,18,20,22,29(37),30(35),31,33-tridecaene-23-carboxylic acid, ... (6 entities in total) |
| Functional Keywords | myeloid cell leukemia 1, mcl-1, b-cell lymphoma 2, bcl-2, bh3 mimetic, protein-protein interaction, modulator, apoptosis, cancer, leukemia, myeloma, lymphoma, signaling protein |
| Biological source | Escherichia coli More |
| Total number of polymer chains | 1 |
| Total formula weight | 58567.61 |
| Authors | |
| Primary citation | Velter, I.A.,Lento, W.,Peschiulli, A.,Reuillon, T.D.,Ferrer, S.,Orgaz-Gordillo, S.,Buijnsters, P.,De Boeck, B.C.A.G.,Demin, S.,Van Roosbroeck, Y.,Jouffroy, M.,Vos, A.,Miller, B.,Shaffer, P.,Koo, S.J.,Dominguez Blanco, M.,McQueen, L.,Altrocchi, C.,Bueters, R.,Vinken, P.,Bekkers, M.,Steyvers, H.,Guttke, C.,Walker, D.,Bauser, M.,Wilson, D.M.,Philippar, U.,Rombouts, F.J.R. In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties. J.Med.Chem., 68:16989-17029, 2025 Cited by PubMed Abstract: Myeloid Cell Leukemia 1, or MCL-1, is an anti-apoptotic protein belonging to the BCL-2 family of proteins, which regulate the mitochondrial pathway of cellular apoptosis via binding of pro- and anti-apoptotic family members. Genetic amplification and overexpression of MCL-1 is one mechanism cancer cells utilize to avoid death and thus MCL-1 has emerged as an attractive target for cancer treatment. Herein, we describe our strategy and medicinal chemistry efforts to identify best-in-class MCL-1 inhibitors with high cytotoxic potency and improved biorelevant solubility while aiming to maximize therapeutic index versus on-target toxicity via IV dosing. These efforts led to the discovery of JNJ-78394355: a highly efficient anti-tumor agent, as demonstrated by the in vivo studies in human-xenograft mouse models of acute myeloid leukemia (AML) and multiple myeloma (MM). PubMed: 40825222DOI: 10.1021/acs.jmedchem.4c03166 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.24 Å) |
Structure validation
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