Identification of MRTX1133: A Noncovalent, Potent, and Selective KRASG12D Inhibitor

Introduction

• KRAS as a Drug Target

  • Mutant KRAS is a significant target for cancer treatment.
  • Previous difficulties due to high affinity of KRAS for GDP/GTP and lack of binding pockets.
  • Irreversible KRAS G12C inhibitors have been successful but rely on covalent bonding with Cys12.
  • KRAS G12D mutation is common, lacks reactive residues, requiring new inhibitor approaches.

• Current KRAS Inhibitors

  • New class of inhibitors targeting pocket between switch I and II showed limited cellular activity.
  • Cyclic peptide inhibitors for KRAS G12D have better biochemical activity but limited cellular potency.

Development of MRTX1133

• Discovery and Optimization
  • MRTX1133: potent, selective, noncovalent KRAS G12D inhibitor with high binding affinity and in vivo efficacy.
  • Initial uncertainty about achieving KRAS G12D inhibition with noncovalent inhibitors.
  • Focused on maximizing inhibitor moieties to enhance binding affinity.

Results and Discussion

• Structure-Based Optimization

  • Used pyrido[4,3-d]pyrimidine scaffold as the base structure.
  • Compound 5B without cyanomethyl group showed better binding affinity.
  • Crystal structure analysis informed further modifications.

• Key Findings

  • Protonated piperazinyl group forms ionic pair with Asp12, improving selectivity over wild-type KRAS.
  • Identified three vectors (protonated piperazinyl, pyrrolidinyl moiety, C7-naphthyl) to enhance affinity.

• Optimization Strategies

  • Rigidification improved binding and selectivity.
  • Adjustments at the C4 and C2 positions led to more potent inhibitors.
  • 8-ethynyl substituent was particularly effective.

In Vivo Efficacy

• MRTX1133 Potency

  • Exceptional binding affinity and selectivity.
  • Inhibits KRAS G12D signaling and shows in vivo antitumor efficacy.

• Pharmacokinetics

  • MRTX1133 showed sustained plasma exposure and significant tumor growth inhibition in mouse models.

Chemistry

• Synthesis of MRTX1133
  • Detailed synthetic process involving chlorination, selective substitution, and deprotections.

Conclusion

• Significance of MRTX1133
  • First report of a small molecule inhibitor with robust in vivo efficacy against KRAS G12D.
  • Potential advancement for therapeutic approaches against this previously undruggable target.
  • Future work will focus on comprehensive pharmacological characterization.

Experimental Section

• Details on chemical analysis methods (NMR, HPLC, LC-MS) and synthesis procedures for compound testing.

Supporting Information

• Additional experimental procedures and data available online, including assay protocols and chemical analysis references.