Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• ATR is crucial for maintaining genome stability via the DNA damage response (DDR).
• ATR inhibition offers a synthetic lethality approach for treating cancers with DDR mutations or deficiencies.
• Targeting ATR presents a promising therapeutic strategy for specific cancer types.

Purpose of the Study:

• To discover and characterize YY2201, a novel and potent ATR inhibitor.
• To evaluate the preclinical efficacy and safety profile of YY2201.
• To assess YY2201's potential as a cancer therapeutic agent, both as a monotherapy and in combination therapy.

Main Methods:

• Discovery and preclinical evaluation of YY2201, a novel ATR inhibitor.
• Assessment of in vitro and in vivo anti-cancer activity across various cancer types.
• Comparative efficacy study of YY2201 versus AZD6738 in a lung cancer xenograft model.
• Evaluation of YY2201 in combination with chemotherapy in vivo.

Main Results:

• YY2201 demonstrated high potency and selectivity as an ATR inhibitor with favorable ADME, safety, and pharmacokinetic profiles.
• YY2201 effectively inhibited tumor progression in vitro and in vivo across a broad spectrum of cancers.
• YY2201 exhibited superior in vivo anticancer efficacy and a better therapeutic index than AZD6738 in a lung cancer model.
• YY2201 showed potent cancer suppression effects when combined with chemotherapy in vivo.

Conclusions:

• YY2201 is a potent and selective ATR inhibitor with promising preclinical anti-cancer activity.
• YY2201 demonstrates superior efficacy and a favorable therapeutic index compared to existing agents in preclinical models.
• YY2201 warrants further clinical investigation for the treatment of cancers with DDR defects, as evidenced by FDA approval for an IND application.