fosun pharma: second-generation trk inhibitor fcn-098 clinically approved
fcn-098 is a highly active, selective, oral second-generation small-molecule tropomyosin receptor kinase (trka, trkb, and trkc) inhibitor. trka, trkb, and trkc are encoded by ntrk1, ntrk2, and ntrk3 genes, respectively. ntrk gene fusions with partner genes of chromosomal rearrangements produce constitutively-activated chimeric trk fusion protein, thus activating downstream signaling pathways and promoting the proliferation and survival of tumor cells.
the mutations in trk domain alter the conformation of the kinase domain or its affinity for atp binding, thereby interfering with its effective binding to atp-competitive inhibitors, such as first-generation trk inhibitors, and subsequently causing resistance to first-generation trk inhibitors. these mutations lead to the substitution of amino acids in the three major regions of trk, including solvent-front mutations (sf), gatekeeper mutations (gf), and xdfg motif mutations. fcn-098 competitively binds to the kinase domain of wild-type or drug-resistant mutant trk with atp, which inhibits the phosphorylation of trk fusion protein and its downstream erk1/2 protein, thus inhibiting tumor growth.
so far, 2 first-generation trk inhibitors, larotrectinib from bayer/loxo and entrectinib from roche/ignyta, are clinically available worldwide. no second-generation trk inhibitor has been authorized for marketing.
previously, the phase i clinical study on fcn-011 capsules, a first-generation trk inhibitor independently developed by fochon pharmaceuticals, has completed the administration in the first subject.
about fochon pharmaceuticals
chongqing fochon pharmaceutical research co., ltd., jointly established by a group of overseas scientists as well as shanghai fosun pharmaceutical co., ltd. and its member enterprises in 2009, is a high-tech enterprise committed to the research and development of first-in-class small-molecule targeted drugs with proprietary intellectual property rights. it is an innovation-driven and efficient operation with bases in "two countries and three regions" in chongqing, shanghai, and san francisco bay area, and continuously pursues excellence with chinese power grafted to global resources. the eternal mission of fochon pharmaceuticals is to benefit global patients with high-quality new drugs.
fochon pharmaceuticals focuses on the research on innovator drugs that are urgently needed for anti-tumor and metabolic diseases in clinical practice. by now, fochon pharmaceuticals has successfully pushed 10 projects into the clinical studies, including 1 project in phase iii clinical study, 3 projects in phase ii clinical studies, and 6 projects in phase i clinical studies, meanwhile, there are another 6-7 projects in preclinical studies.