9PW7
Myeloid cell leukemia-1 (Mcl-1) complexed with compound 13
This is a non-PDB format compatible entry.
Summary for 9PW7
| Entry DOI | 10.2210/pdb9pw7/pdb |
| Descriptor | Maltodextrin-binding protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (2S,4R,5S,12P,23R)-11-chloro-7-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-27,28-dimethoxy-4,15-dimethyl-32-oxo-19-oxa-2,5,15,16,23-pentaazaheptacyclo[21.6.1.1~2,6~.1~5,8~.0~12,31~.0~13,17~.0~26,30~]dotriaconta-1(30),6,8(31),9,11,13,16,24,26,28-decaene-24-carboxylic acid (non-preferred name), ... (4 entities in total) |
| Functional Keywords | mcl-1, cancer, drug discovery, fbdd, apoptosis |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 58557.09 |
| Authors | |
| Primary citation | Tarr, J.C.,Jeon, K.,Veerasamy, N.,Aichinger, M.,Salovich, J.M.,Zhao, B.,Sensintaffar, J.L.,Arnhof, H.,Wunberg, T.,Sgubin, D.,Arnold, A.,Vekariya, R.H.,Christov, P.P.,Kim, K.,Fuchs, J.E.,Karier, P.,Betzemeier, B.,Van Meveren, M.,Miriyala, N.,Olejniczak, E.T.,Engelhardt, H.,Lee, T.,McConnell, D.,Fesik, S.W. Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model. J.Med.Chem., 68:18553-18578, 2025 Cited by PubMed Abstract: The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the ()-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors. PubMed: 40864607DOI: 10.1021/acs.jmedchem.5c01376 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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