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Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Aug 08; Vol. 62 (15), pp. 6913-6924. Date of Electronic Publication: 2019 Jul 24. - Publication Year :
- 2019
-
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.
- Subjects :
- Cell Survival drug effects
HCT116 Cells
HeLa Cells
Humans
Protein Structure, Tertiary
Pyrimidines pharmacology
Structure-Activity Relationship
Thiophenes pharmacology
Cell Survival physiology
Drug Discovery methods
Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Pyrimidines chemistry
Pyrimidines metabolism
Thiophenes chemistry
Thiophenes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31339316
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b00134