9PW6
Myeloid cell leukemia-1 (Mcl-1) complexed with compound 8
This is a non-PDB format compatible entry.
Summary for 9PW6
| Entry DOI | 10.2210/pdb9pw6/pdb |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, 7-[(4R,5S,6P)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl]-1-(2-methoxyethyl)-5-methyl-1H-indole-2-carboxylic acid (3 entities in total) |
| Functional Keywords | mcl-1, cancer, drug discovery, apoptosis |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 36443.25 |
| 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 (2.068 Å) |
Structure validation
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