The cancers caused by mutations accounts for about 30% of human cancers, among which the cancers caused by KRAS mutationaccount for 85% of all RAS mutations, and is prevalent in fatal cancers such as pancreatic cancers (90%), colorectal carcinomas (30%

~50%), and non-small cell lung cancers (15%~20%). The common KRAS mutation sites include G12 (83%), G13 (14%), and Q61 

(2%), the main mutation types include G12D (33%), G12V (23%), G12C (11%), and G13D (12%). KRAS protein is essentially a small enzyme that is inactivated (KRAS OFF) when it binds to GDP in cells. When it binds to GTP, it is activated (KRAS ON) and affects multiple downstream signaling pathways including MPAK, PI3K, Ral GEFs, etc. Therefore, the KRAS protein plays an important role in regulating cell growth, proliferation, differentiation, apoptosis, and other life activities. The mutation of KRAS is closely related to the occurrence of tumors. After mutation, KRAS binds to GTP without stimulation of external signal transduction and maintains a sustained activation state, which affects downstream signaling pathways, leads to extensive cell proliferation and malignant transformation, and also impacts the tumor microenvironment. Therefore, the targeted KRAS mutant protein is an important means of treating cancer. At present, various KRAS covalent inhibitors are in the clinical development and application stage. Among them, G12C inhibitors such as Sotorasib from Amgen and Adarasib from Mirati Therapeutics, Inc. have been approved for marketing. However, research on inhibitors of common mutants such as KRAS G12D and KRAS G12V still faces significant challenges, and the drug resistance and other issues that come with approved drugs are also new difficulties in the research of KRAS inhibitors.

      Applied Pharmaceutical Science, Inc. has developed pan-KRAS inhibitors that have inhibitory effects on multiple mutations of KRAS through the differentiated drug design method based on structure. This not only has the potential to overcome the resistance problem of existing covalent inhibitors for KRAS, but also acts on the activated state of KRAS, preventing KRAS that is already in an activated state from exerting biological effects and cutting off the downstream signal transmission of KRAS. Compared with KRAS (OFF) inhibitors, we have developed pan-KRAS inhibitors based on more efficient activity inhibition for KRAS and a wider range of indications. We have obtained highly active lead compounds and are further accelerating its progress to PCC, with the hope of achieving IND quickly.