8G3U

MBP-Mcl1 in complex with ligand 21

Summary for 8G3U

• Entry DOI: 10.2210/pdb8g3u/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, 1,2-ETHANEDIOL, ... (5 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: 58578.72

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

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: 37114951
DOI: 10.1021/acs.jmedchem.2c01953

Experimental method

X-RAY DIFFRACTION (1.94 Å)