8G3T
MBP-Mcl1 in complex with ligand 12
Summary for 8G3T
| Entry DOI | 10.2210/pdb8g3t/pdb |
| Related PRD ID | PRD_900001 |
| Descriptor | Maltodextrin-binding protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, FORMIC 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, physicochemical properties, adme properties, cardiotoxicity, therapeutic window |
| Biological source | Serratia sp. FS14 More |
| Total number of polymer chains | 1 |
| Total formula weight | 58408.47 |
| Authors | Miller, B.R.,Shaffer, P. (deposition date: 2023-02-08, release date: 2023-05-17, Last modification date: 2024-05-22) |
| Primary citation | Romanov-Michailidis, F.,Hsiao, C.C.,Urner, L.M.,Jerhaoui, S.,Surkyn, M.,Miller, B.,Vos, A.,Dominguez Blanco, M.,Bueters, R.,Vinken, P.,Bekkers, M.,Walker, D.,Pietrak, B.,Eyckmans, W.,Dores-Sousa, J.L.,Joo Koo, S.,Lento, W.,Bauser, M.,Philippar, U.,Rombouts, F.J.R. Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies. J.Med.Chem., 66:6122-6148, 2023 Cited by PubMed Abstract: Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model. PubMed: 37114951DOI: 10.1021/acs.jmedchem.2c01953 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.83 Å) |
Structure validation
Download full validation report
