Abstract
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Highlights
Mutant KRAS has been recognized as an attractive drug target for the treatment of a number of cancers for many decades.[1−4] the high affinity of KRAS for GDP/GTP and the lack of any other apparent binding pocket have significantly hampered the development of KRAS inhibitors until recently.[1,4] The identification and subsequent clinical success of irreversible KRASG12C inhibitors that occupy the induced switch II pocket has been a very important breakthrough.[5−7]their inhibitory activity relies on a reactive warhead forming a stable covalent bond with the mutant Cys[12]
Compound 5A was inactive, analog 5B without the cyanomethyl group demonstrated a KD of 3.5 μM in a KRASG12D SPR assay with GDP-loaded KRASG12D (Figure 2)
While the cyanomethyl group on the 3-position of the piperazine ring was found beneficial for irreversible KRASG12C inhibitors[5] by displacing a water molecule close to Gly[10] and enhancing the reactivity of the acrylamide warhead, compounds 5A and 5B suggested that a different approach would be needed to enhance KRASG12D binding affinity in this region of the molecule for the pyrido[4,3-d]pyrimidine core
Summary
Mutant KRAS has been recognized as an attractive drug target for the treatment of a number of cancers for many decades.[1−4] the high affinity of KRAS for GDP/GTP and the lack of any other apparent binding pocket have significantly hampered the development of KRAS inhibitors until recently.[1,4] The identification and subsequent clinical success of irreversible KRASG12C inhibitors that occupy the induced switch II pocket has been a very important breakthrough.[5−7]. We focused on maximizing the contribution of each moiety of the inhibitor to increase affinity, expecting that greater occupancy of the induced switch II pocket would lead to sustained functional suppression of KRAS pathway signaling in cellular and tumor environments harboring the KRASG12D mutation sufficient for antitumor efficacy
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