6QXJ

Structure of MBP-Mcl-1 in complex with compound 6a

Summary for 6QXJ

• Entry DOI: 10.2210/pdb6qxj/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (2~{R})-2-[[6-ethyl-5-(1~{H}-indol-5-yl)thieno[2,3-d]pyrimidin-4-yl]amino]propanoic acid, ... (5 entities in total)
• Functional Keywords: apoptosis-inhibitor complex, mcl1, small molecule inhibitor, mbp, apoptosis
• Biological source: Escherichia coli O157:H7; More
• Total number of polymer chains: 1
• Total formula weight: 57957.59

Authors

Dokurno, P.,Szlavik, Z.,Ondi, L.,Csekei, M.,Paczal, A.,Szabo, Z.B.,Radics, G.,Murray, J.,Davidson, J.,Chen, I.,Davis, B.,Hubbard, R.E.,Pedder, C.,Surgenor, A.E.,Smith, J.,Robertson, A.,LeToumelin-Braizat, G.,Cauquil, N.,Zarka, M.,Demarles, D.,Perron-Sierra, F.,Geneste, O.,Kotschy, A. (deposition date: 2019-03-07, release date: 2019-08-07, Last modification date: 2024-01-24)

Primary citation

Szlavik, Z.,Ondi, L.,Csekei, M.,Paczal, A.,Szabo, Z.B.,Radics, G.,Murray, J.,Davidson, J.,Chen, I.,Davis, B.,Hubbard, R.E.,Pedder, C.,Dokurno, P.,Surgenor, A.,Smith, J.,Robertson, A.,LeToumelin-Braizat, G.,Cauquil, N.,Zarka, M.,Demarles, D.,Perron-Sierra, F.,Claperon, A.,Colland, F.,Geneste, O.,Kotschy, A.
Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.
J.Med.Chem., 62:6913-6924, 2019

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

PubMed: 31339316
DOI: 10.1021/acs.jmedchem.9b00134

Experimental method

X-RAY DIFFRACTION (1.7 Å)