Structure-based inhibitor design of mutant RAS proteins—a paradigm shift

Abstract

As a member of small GTPase family, KRAS protein is a key physiological modulator of various cellular activities including proliferation. However, mutations of KRAS present in numerous cancer types, most frequently in pancreatic (> 60%), colorectal (> 40%), and lung cancers, drive oncogenic processes through overactivation of proliferation. The G12C mutation of KRAS protein is especially abundant in the case of these types of malignancies. Despite its key importance in human disease, KRAS was assumed to be non-druggable for a long time since the protein seemingly lacks potential drug-binding pockets except the nucleotide-binding site, which is difficult to be targeted due to the high affinity of KRAS for both GDP and GTP. Recently, a new approach broke the ice and provided evidence that upon covalent targeting of the G12C mutant KRAS, a highly dynamic pocket was revealed. This novel targeting is especially important since it serves with an inherent solution for drug selectivity. Based on these results, various structure-based drug design projects have been launched to develop selective KRAS mutant inhibitors. In addition to the covalent modification strategy mostly applicable for G12C mutation, different innovative solutions have been suggested for the other frequently occurring oncogenic G12 mutants. Here we summarize the latest advances of this field, provide perspectives for novel approaches, and highlight the special properties of KRAS, which might issue some new challenges. Electronic supplementary material The online version of this article (10.1007/s10555-020-09914-6) contains supplementary material, which is available to authorized users.

KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments

“…9). 45 On the basis of these findings, we propose the choice of the second-line drug(s) depending on the secondary mutations that emerge on acquiring resistance (Fig. 6B).…”

Defining An Expanded RAS Conformational Landscape Based on Over 700 Experimentally Determined Structures of KRAS, NRAS, and HRAS

“…In addition, we found that the SP2 inhibitor site is only present in structures with Y71 exposed to solvent, while the SP12 inhibitors site appears in structures with Y71 buried into the protein core. Although this trend for Y71 was previously described for a select few SP12 inhibitor-bound structures 8,38 , the consistency of this finding among many inhibitor-bound structures suggests it is an essential determinant of SP2 and SP12 druggability.…”

“…Importantly, the presence of SP12 and SP2 sites correlated with different side chain χ1 (chi1) dihedrals (i.e., rotamers) for residue Y71 in SW2. The SP12 inhibitor-bound structures prefer a ~60°, or gauche-plus (g+) rotamer of Y71, which buries Y71 within the RAS domain, exposing the SP12 site and occluding the SP2 site; this trend for Y71 was previously described for a select few SP12 inhibitor-bound structures 8,38 . The SP2 inhibitor -bound structures, by contrast, contain a ~300°, or gauche-minus (g-) rotamer of Y71, which exposes Y71 to solvent thereby opening the SP2 site and occluding the SP12 site (Fig.…”

“…Clustering RAS Conformations. Several RAS conformations have been previously described based on the arrangement of SW1 (residues [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and SW2 (residues . For SW1, the conformations are named by their nucleotide state and include: the "canonical" GDP-bound 25,26 , nucleotide-free 6,15 , and GTP-bound "state 1" and "state 2" (Fig.…”

Understand KRAS and the Quest for Anti-Cancer Drugs

“…Recently, many studies have focused on attempts that target exchange nucleotide. Recent studies have focused on attempts to block nucleotide exchange [ 8 , 9 ]. Several structure-based inhibitors (e.g., SML-8-73-1, H-REV107 peptide, BAY-293, or BI-3406) have been reported to target the guanine nucleotide binding site of the KRAS mutant and inhibit GDP to GTP exchange [ 10 , 11 , 12 , 13 ].…”