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Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy
Bo Chen1, Xiaofeng Liu1, Tong Mu1
1Medicinal Chemistry, China Innovation Center of Roche, Shanghai 201203, China.
Abstract:
PKMYT1 is a crucial regulator of the cell cycle, particularly involved in the G2/M transition through the inhibitory phosphorylation of CDK1, and is a promising therapeutic target for cancer therapy. Data mining in the Roche kinome screen database identified a hit characterized by 100% PKMYT1 inhibitory activity at a 10 μM concentration, which was further validated with a PKMYT1 enzymatic assay showing double-digit nanomolar potency. The hit featured a quinolinone central core and a phenol headgroup. The replacement of the problematic phenol headgroup with an indazole moiety induced a flip in the kinase hinge cysteine and glycine residues, resulting in a series of derivatives with enhanced potency, superior kinome selectivity, and no GSH flag. Further structural fine-tuning led to the discovery of compound 36, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.
Insights
Researchers identified a novel inhibitor targeting PKMYT1 (Protein Kinase Myristoylated Alanine Rich C Kinase 1), a key cell cycle regulator. This new compound shows potent and selective inhibition, offering promise for effective cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Protein Kinase Myristoylated Alanine Rich C Kinase 1 (PKMYT1) is vital for cell cycle regulation, specifically the G2/M transition.
- Dysregulation of PKMYT1 is implicated in cancer, making it a significant therapeutic target.
Purpose of the Study:
- To identify and develop novel, potent, and selective inhibitors of PKMYT1 for potential cancer therapy.
- To optimize initial hits through structure-activity relationship studies.
Main Methods:
- Data mining of the Roche kinome screen database to identify PKMYT1 inhibitors.
- Enzymatic assays to determine inhibitor potency and selectivity.
- Structure-based drug design and chemical synthesis for derivative optimization.
Main Results:
- An initial hit with 100% PKMYT1 inhibition was identified, later optimized to double-digit nanomolar potency.
- Modification of the lead compound, including replacing a phenol headgroup with an indazole moiety, enhanced potency and selectivity.
- Compound 36 emerged as a highly selective and potent PKMYT1 inhibitor with favorable oral pharmacokinetics and demonstrated in vivo antitumor efficacy.
Conclusions:
- Novel indazole-containing quinolinone derivatives represent a promising class of PKMYT1 inhibitors.
- Compound 36 is a potential drug candidate for cancer treatment due to its potency, selectivity, and pharmacokinetic properties.
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