Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer

Abstract

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS

“…Recently, several macromolecules [3][4][5][6][7] and compounds [8][9][10][11][12][13] have been developed that influence the function of RAS family members. Nevertheless, only the G12C mutation of KRAS has been specifically targeted by small molecules by virtue of covalent binding of the compounds to the mutant cysteine [14][15][16][17][18][19][20][21] . Several small molecules are now in clinical trials 22 .…”

KRasG12C inhibitors in clinical trials: a short historical perspective

“…5a). 37,38 The 8-chloronaphtyl substituent of MRTX849 fills the lipophilic pocket as previously described for compound 4 Fell (11). Additional hydrogen bonds between the cyanomethyl group and the backbone NH of Gly10 as well as between the pyrrolidine moiety and Glu62 were observed (Fig.…”

Small molecule inhibitors of RAS proteins with oncogenic mutations

“…They also tried to revisiting the acrylamide moiety of the compounds and found 2-fluoroacrylamide as an enhanced warhead. This was also attached to their compound MRTX849 ( Table 5, SI Table 1) [138][139][140] which is now in phase I/II clinical trial in treatment of cancers with KRAS-G12C mutation [142,142].…”