Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Phosphoinositide-3-kinases (PI3K) are crucial lipid kinases regulating cell proliferation, migration, and differentiation.
• PI3K pathway dysregulation is implicated in numerous human cancers, making it a key therapeutic target.
• Targeting PI3K offers a promising strategy for developing novel anti-cancer therapeutics.

Purpose of the Study:

• To rapidly identify and characterize novel inhibitors of the PI3K pathway.
• To evaluate the pharmacokinetic properties and in vivo efficacy of a newly identified compound, ETP-46992.
• To assess the anti-tumor activity of ETP-46992 in relevant preclinical cancer models.

Main Methods:

• Medicinal chemistry efforts focused on the 2-aminocarbonyl imidazo [1,2-a] pyrazine chemical series.
• Pharmacokinetic (PK) profiling to assess drug-like properties.
• In vivo efficacy studies using a K-Ras(G12V) driven GEMM mouse tumor model and PI3K-deregulated BT474 xenograft models.

Main Results:

• Rapid identification of ETP-46992 with suitable pharmacokinetic properties.
• ETP-46992 demonstrated significant tumor growth inhibition in a GEMM mouse model harboring a K-Ras(G12V) mutation.
• ETP-46992 also exhibited efficacy in BT474 tumor xenograft models with deregulated PI3K signaling.

Conclusions:

• ETP-46992 is a potent PI3K inhibitor with favorable PK properties.
• The compound shows significant anti-tumor activity in preclinical models of K-Ras mutated cancers and PI3K pathway-driven tumors.
• ETP-46992 represents a promising therapeutic candidate for cancers with PI3K pathway alterations.