Abstract
CCNE1 amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for CCNE1 amplification holds promise for the treatment of CCNE1-amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound 8ma exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the CCNE1-amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.
MeSH terms
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Breast Neoplasms* / drug therapy
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Breast Neoplasms* / pathology
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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Crystallography, X-Ray
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Cyclin E* / metabolism
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Drug Design*
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Drug Screening Assays, Antitumor
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Female
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Humans
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Membrane Proteins
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Oncogene Proteins / antagonists & inhibitors
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
Substances
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PKMYT1 protein, human
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Antineoplastic Agents
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CCNE1 protein, human
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Cyclin E
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Oncogene Proteins
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Protein Kinase Inhibitors
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Protein-Tyrosine Kinases
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Membrane Proteins
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Protein Serine-Threonine Kinases