Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Alterations in the PI3K/Akt/mTOR (PAM) pathway are common drivers of various human cancers.
• Targeting key kinases within the PAM pathway, such as p70S6k and Akt, is a promising therapeutic strategy.

Purpose of the Study:

• To discover novel dual inhibitors targeting both p70S6k and Akt kinases.
• To develop potent and selective compounds for the treatment of PAM pathway-driven tumors.

Main Methods:

• Screening of a proprietary kinase inhibitor library to identify initial hit compounds.
• Structure-based drug design and medicinal chemistry optimization.
• Biochemical and cellular assays to evaluate kinase inhibition and activity.
• In vivo studies in animal models to assess anti-tumor efficacy and pharmacokinetic profiles.

Main Results:

• Identification of 4-benzylamino-quinazoline-8-carboxylic acid amide 1 as a starting point with sub-micromolar p70S6k activity.
• Discovery of M2698, a novel quinazoline carboxamide dual p70S6k/Akt inhibitor.
• M2698 demonstrated kinase selectivity, favorable drug-like properties (physical, chemical, DMPK), oral bioavailability, and good tolerability.
• M2698 exhibited significant tumor control in vivo across multiple models of PAM pathway-driven cancers.

Conclusions:

• Novel quinazoline carboxamides represent a promising class of dual p70S6k/Akt inhibitors.
• M2698 is a potent, selective, orally available drug candidate with demonstrated anti-tumor activity in preclinical models.
• These findings support the further development of M2698 for treating cancers driven by the PI3K/Akt/mTOR pathway.