During the past decade, first-line use of imatinib has benefited GIST patients. GIST patients develop imatinib-resistance due to secondary mutation in cKIT after 20-24 months of drug treatment. Although the 2nd line drugs such as, sunitinib is effective, activation loop mutations quickly overcame their potent inhibitory effects. Moreover, these drugs have numerous potential side-effects. Even with the newly launched sorafenib and nilotinib for advanced GIST, the long term clinical outcome was still not very promising for GIST patients, due to the rapid development of drug resistance on cKIT.
IBPR has identified a series of novel cKIT inhibitors, the BPRCKJ series, which exhibited potent cKIT kinase activity inhibition. To evaluate the potential of BPRCKJ compounds as novel cKIT inhibitors against GIST, eight different imatinib-resistant mutated cKITs were selected to examine the inhibitory activities of BPRCKJ series. The results showed that BPRCKJ series has a broad spectrum activity against various forms of imatinib-resistant mutant c-KITs. Most importantly, the ability to overcome imatinib- and sunitinib-resistant mutant cKITs is demonstrated.
Through the comprehensive SAR study, we had identified BPRCKJ001 as a potential candidate, which was shown to strongly inhibit the enzymatic activities of several mutant c-KIT. BPRCKJ001 also effectively inhibited three GIST sensitive and resistant cell lines with IC50 values below 20 nM. It is interesting to note that BPRCKJ001 is 10-times and 400-times more potent than sunitinib in GIST430 cells and sunitinib-resistant cell lines (GIST48), respectively. The Western blot analyses also clearly showed that BPRCKJ001 can suppress the cKIT phosphorylation and downstream AKT phosphorylation more effectively than imatinib and sunitinib in GIST430 cells.
BPRCKJ001 had shown excellent in vitro effects, targeting against both imatinib- and sunitinib-resistant mutants in both enzymatic and cellular systems. More importantly, BPRCKJ001 also demonstrated in vivo efficacy by oral administration in GIST430 xenograft model. These results indicate that CKJBPR001 series has reasonable pharmaceutical properties to be developed as a potential cKIT inhibitor
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All authors have declared no conflicts of interest.