Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS^G12D Mutation

Abstract

Effective oral therapies are urgently required to treat KRASG12D mutant cancers. Therefore, synthesis and screening were performed for 38 prodrugs of MRTX1133 to identify an oral prodrug of MRTX1133, a KRASG12D mutant protein-specific inhibitor. In vitro and in vivo evaluations revealed prodrug 9 as the first orally available KRASG12D inhibitor. Prodrug 9 exhibited improved pharmacokinetic properties for the parent compound in mice and was efficacious in a KRASG12D mutant xenograft mouse tumor model after oral administration.

Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer

“…As the development of KRAS G12C -targeted therapeutics has progressed at a rapid pace, there have been some notable achievements in the development of drugs for KRAS G12D . In preclinical trials, MRTX1133, a KRAS G12D inhibitor, mediated the apparent regression of KRAS G12D mutant pancreatic ductal adenocarcinoma [50][51][52]. Currently, MRTX1133 is in a clinical trial to evaluate its safety, tolerability, and antitumor activity in patients with advanced solid tumor malignancies harboring KRAS G12D mutations (ClinicalTrials.gov Identifier: NCT05737706).…”

Targeting KRAS in pancreatic cancer

“…In combination with relatively poor bioavailability, survival of cells at higher concentrations of MRTX1133, and possible development of chemoresistance this drug may experience limitations in clinics. An oral prodrug of MRTX1133, prodrug 9, exhibited better bioavailability in mice and was active in a KRAS G12D mutant xenograft mouse tumor model [ 46 ]. A study employing isogenic cell lines that express a single KRAS allele demonstrated that MRTX1133 also exhibited significant activity against KRAS mutations including G12C, G12V, G13D, and wildtype KRAS but spare HRAS and NRAS because the binding to H95 of KRAS, a residue that is not conserved in HRAS and NRAS, is essential for MRTX1133 activity [ 45 ].…”