Drugging K-Ras through covalent inhibitors: Mission possible?

Ras, whose mutants are present in approximately 30% of human tumours, is one of the most important oncogenes. Drugging Ras is thus regarded as the quest for the Holy Grail in cancer therapeutics development. Despite more than three decades of efforts, drug discovery targeting Ras constantly fails, rendering Ras undruggable, due to its smooth surface and picomolar affinity towards guanosine substrates. The most frequently mutated isoform of Ras is K-Ras, accounting for >85% of Ras-driven cancers, and one majority of them is the G12C mutation. Recent advances in structural biology shed light on drugging Ras, and one of the cutting-edge breakthroughs is the design of covalent G12C-specific inhibitors targeting the mutated cysteine. This type of inhibitor can be classified into substrate-competitive orthosteric inhibitors and non-competitive allosteric inhibitors. They display improved selectivity and enhanced potency due to their G12-specific and irreversible covalent binding nature. Thus, they represent a new hope for revolutionizing the conventional characterization of Ras as "undruggable" and pave a promising avenue for further drug discovery. Here, we provide comprehensive structural and medicinal chemical insights into K-Ras covalent inhibitors specific for the G12C mutant. We first present an in-depth analysis of the conformations of the inhibitor binding pockets. Then, all the latest covalent ligands selectively inhibiting K-Ras are reviewed. Finally, we examine the current challenges faced by this new class of anti-Ras inhibitors.