KRAS proteins are small GTPase enzymes that function as molecular switches: they respond to upstream EGFR activation and regulate the downstream mitogen activated protein kinase (MAPK) and PI3K/mTOR pathways, controlling cell proliferation, differentiation, and survival. Oncogenic mutation of KRAS is closely linked to tumorigenesis. For the longest time, KRAS was considered an undruggable target until the Shokat laboratory successfully developed a series of compounds that covalently and irreversibly bound to the cysteine residue of the KRAS G12C (glycine-to-cysteine substitution) mutant. Unfortunately, the most potent compound containing an acrylamide warhead was incapable of engaging KRAS G12C in cells even at a relatively high dose and with long incubation times. Structural optimization of this scaffold led to ARS-853, the first potent KRAS inhibitor shown to selectively and directly inhibit KRAS in cells ; however, its low metabolic plasma stability and poor bioavailability stalled further development and prevented its preclinical evaluation. Efforts to improve the physiochemical properties and pharmacokinetic parameters of ARS-853 resulted in a new generation of KRAS G12C inhibitors capable of exploiting an allosteric pocket. The substituted piperazine ring incorporates to scaffolds, like quinazoline core, quinazolinone core, or tetrahydropyridopyrimidine core occupying the allosteric pocket for enhanced potency and provided ADME properties suitable for further optimization. ARS-1620, one of the most potent compounds from the newly developed series was the first KRAS G12C inhibitor with efficacy in vivo in patient-derived xenografts. ARS-1620 is potent, selective, orally bioavailable, and well-tolerated in mice. The compound exhibited both in vitro and in vivo potency and has therapeutic potential as a drug candidate. ARS1620 can lead to the presentation of drug-modified neoantigens by class I major histocompatibility complex (MHC). A bispecific T cell engager that recognizes these neoantigens elicits a cytotoxic T cell response against KRASG12C cells, including those resistant to direct KRAS G12C inhibition. Efforts to identify molecules capable of targeting the GTP-bound, active state of KRAS led to the discovery of a cryptic groove adjacent to the allosteric switch II pocket created by rotation of His95. Adagrasib (MRTX849) and sotorasib (AMG510) were designed to fit into this binding pocket and engage in interaction with His95 in order to maximize potency. Approved by the US FDA in 2021, sotorasib became the first therapy to treat KRAS-mutant cancers, particularly KRAS G12C mutant non-small-cell lung cancer (NSCLC). The structurally novel covalent KRAS G12C inhibitor, JDQ443, resulted from a preliminary in silico screening and was developed from a distinct pharmacophore a unique 5-methylpyrazole core with a spiro-azetidine linker. JDQ443 demonstrated potent and selective antitumor activity in cell lines and in vivo models and unlike other KRAS G12C inhibitors only weakly interacted with His95. Chloro and methyl substituents on the indazole ring optimally fill the hydrophobic region, while the rigid spirocyclic linker orients the acrylamide warhead towards Cys12 allowing the amide carbonyl to form Hbond interactions with the side chain of Lys16. JDQ443 is currently in clinical development as a monotherapy and in combination with either the SH2 containing protein tyrosine phosphatase-2 (SHP2) inhibitor TNO155, the anti-PD-1 monoclonal antibody tislelizumab, or both in advanced duodenal cancer. To date, a total of twelve irreversible inhibitors of KRAS G12C have entered in clinical trials, including adagrasib (MRTX849, Mirati Therapeutics), sotorasib (AMG510, Amgen), JNJ-74699157 (Janssen), LY 3499446 and LY 3537982 (Eli Lilly), divarasib (GDC-6036; Genentech), D-1553 (InventisBio), JDQ443 (Novartis), BI1823911 (Boehringer Ingelheim), JAB-21822 (Jacobio Pharmaceuticals Group), MK-1084 (Merck) and RMC-6291 (Revolution Medicines) with adagrasib and sotorasib gaining FDA approvals in 2022 and 2021, respectively.