Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor

Area of Science:

• Oncology
• Medicinal Chemistry
• Drug Discovery

Background:

• KRAS-driven cancers represent a significant unmet medical need.
• KRAS G12C inhibitors have shown clinical success, highlighting the therapeutic potential of targeting KRAS mutations.
• KRAS G12D is the most prevalent KRAS mutation, offering a larger patient population for targeted therapies.

Purpose of the Study:

• To discover and develop novel inhibitors targeting the KRAS G12D mutation.
• To overcome the challenges associated with targeting KRAS G12D, particularly achieving sufficient potency and oral bioavailability.
• To identify a KRAS G12D inhibitor with favorable ADME properties for potential clinical development.

Main Methods:

• Structure-based drug design was employed to optimize a weakly potent hit compound.
• Iterative medicinal chemistry efforts focused on enhancing molecular rigidity and balancing polarity.
• Pharmacokinetic studies in nonhuman primates (NHP) were conducted to assess oral exposure.

Main Results:

• Discovery of KRAS G12D inhibitor 23 (INCB159020) with significantly improved potency.
• INCB159020 demonstrated successful oral exposure in nonhuman primate studies.
• Optimization strategies successfully balanced potency with ADME properties required for oral administration.

Conclusions:

• INCB159020 represents a promising KRAS G12D inhibitor with demonstrated oral bioavailability.
• The development of INCB159020 validates structure-based drug design and focused optimization for targeting challenging mutant proteins.
• This discovery holds potential for expanding treatment options for patients with KRAS G12D-mutant cancers.