Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, particularly involving ERK1/2 kinases, is a common driver of tumor progression.
• ERK1/2 kinases represent a critical therapeutic target for various cancers, especially those with specific genetic mutations.

Purpose of the Study:

• To discover and optimize a novel ERK1/2 inhibitor, ASTX029, for therapeutic use in cancer treatment.
• To address challenges such as CYP3A4-mediated metabolism and ensure favorable physicochemical and pharmacokinetic properties for clinical development.

Main Methods:

• Structure-guided optimization of a previously identified isoindolinone lead compound (7).
• Medicinal chemistry efforts focused on improving metabolic stability and drug-like properties.
• Preclinical evaluation of pharmacological activity, including ERK1/2 inhibition and phospho-ERK1/2 (pERK) level suppression.
• Assessment of pharmacokinetic properties to predict human dosing regimens.

Main Results:

• Identification of ASTX029 (15) as a clinical candidate with potent ERK1/2 inhibitory activity.
• ASTX029 demonstrated suppression of pERK levels, indicating pathway modulation.
• The compound exhibited suitable preclinical pharmacokinetic properties, suggesting potential for once-daily dosing in humans.
• ASTX029 has advanced to a Phase I-II clinical trial for advanced solid tumors.

Conclusions:

• ASTX029 is a promising clinical candidate resulting from structure-guided drug design and optimization.
• The drug effectively inhibits ERK1/2 and suppresses downstream signaling, with favorable pharmacokinetics for clinical application.
• Ongoing clinical trials will further evaluate the safety and efficacy of ASTX029 in patients with advanced solid tumors.