FN-1501

We sought to determine whether combination of azacitidine with a FLT3 inhibitor (gilteritinib, quizartinib, LT-850-166, FN-1501 or FF-10101) displayed synergy or antagonism. The results show that combinations that involved non-covalent FLT3 inhibitors, including the two clinically approved drugs gilteritinib and quizartinib were antagonistic. On the other hand combinations with the covalent inhibitor FF-10101 had some range of concentrations where synergy was observed.

In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.

Herein, we describe the discovery of compound LT-540-717 (32), a potent FLT3 inhibitor (IC: 0.62 nM), starting from FN-1501...Furthermore, 32 showed an acceptable bioavailability (F = 33.3% in rat and 72.7% in beagles), a suitable half-life time (T = 3.5 h in rat and T = 11.1 h in beagles), and a satisfactory metabolic stability. In summary, these results show the therapeutic potential of 32 to become a new anti-AML drug, especially for AML harboring dual FLT3 (ITD, TKD) mutations.

FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level.

By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized...In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI < 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.