KRAS is one of the most commonly mutated oncogenes in all human cancers. The frequently occurring G12D mutation had proved undruggable, until this discovery of a modified imidazothiazole compound which prevents GDP displacement by GTP, thus inhibiting KRASâs ability to bind to (and activate) downstream effectors. A compound library was screened in two assays and #87 (with an imidazothiazole scaffold) showed the most promise in preventing GDP displacement (by GTP) and inhibiting KRAS-Raf binding with an IC50 of 61Î¼M.
- Oncogenic mutations in KRAS lead to it being permanently bound by GTP (as opposed to GDP) rendering KRAS constitutively active. The mutated KRAS oncogene is found in approximately 90% of pancreatic cancers (pancreatic adenocarcinoma), 40% of colorectal cancer, 30% of lung cancers, and generally in about 20-30% of all human cancers, with the G12D mutation being the most frequent at approximately 43%, representing nearly 50,000 US patients annually. These cancers are particularly difficult to treat—with a tendency to poor outcomes, due to an association between KRAS mutations and lack of response to EGFR tyrosine kinase inhibitors and chemotherapy.
- Scientists and physicians have long deemed KRAS “undruggable.” This has created numerous attempts to treat KRAS mutated cancers by inhibiting KRAS’s immediate downstream targets, including AstraZeneca’s Selumetinib (a MEK inhibitor), Merck’s MK-2206 (AKT inhibitor), Bayer’s Sorafenib (a pan-RAF inhibitor). Attempts to block Ras signalling by altering its cellular location via inhibitors of post-translational lipid modifications, such as palmitylation, garenylgarenylation and farnesylation, have also failed in clinical trials.
- None of these agents against downstream targets address the driving mutation of the tumor, and most patients develop resistance by upregulating compensatory pathways. However, by focusing directly on inhibiting KRAS activation, this small molecule can prevent KRAS signaling through all of its downstream pathways, thereby offering targeted therapy to a patient population where there is a great unmet need.