Inhibition of RAS: proven and potential vulnerabilities

Abstract

RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.

The Ras Dimer Structure

“…Knowledge of the precise amino acid interaction network of the dimer interface provides novel target sites for anti-cancer drugs that prevent Ras dimerization, which plays a crucial role in signal transduction in vivo. 36 Our study shows for N-Ras that only those dimer models exhibiting an interface involving helices α4 and α5 (dimer category I) are in accordance with all four experimental distances. Dimer category II disagrees with both FRET and EPR distance obtained for position T124 and category III disagrees with the experimentally observed nucleotidenucleotide distance.…”

“…[33][34][35] For targeted development of anti-cancer drugs that break dimers of malfunctioning Ras and thereby inhibit signaling, a detailed understanding of the exact dimer interaction network is desirable. 36 Promising drug targets can be proposed based on atomic level information regarding dimer interactions. However, the exact molecular structure of Ras-dimers remains elusive.…”

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

“…Targeted therapy is also rarely possible since more than 90% of PDAC patients have an activating mutation in the Kirsten rat sarcoma (KRAS) gene, 10 which is the most important driver mutation in this cancer 11 . There is no effective targeted therapy for KRAS mutated cancers, 12 with the novel exception of the p.G12C mutation 13 . Although this variant is quite commonly found in lung cancer it is very rare in PDAC 14 .…”

The Ras dimer structure

“…[37][38][39] For targeted development of anti-cancer drugs that break dimers of malfunctioning Ras and thereby inhibit signaling, a detailed understanding of the exact dimer interaction network is desirable. 40 Promising drug targets can be proposed based on atomic level information regarding dimer interactions. However, the exact molecular structure of Ras-dimers remains elusive.…”

“… 37–39 For targeted development of anti-cancer drugs that break dimers of malfunctioning Ras and thereby inhibit signaling, a detailed understanding of the exact dimer interaction network is desirable. 40 …”