Description
CCT241161 is a novel orally available, pan-RAF inhibitor with anti-SRC activity. CCT241161 blocked growth of BRAF-mutant and NRAS-mutant melanoma cells, inhibiting MEK–ERK, in vitro and in vivo. CCT241161 also prevented growth of xenografts derived from patient tumours with acquired or intrinsic resistance to BRAF and MEK inhibitors. BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs.
Uses
CCT241161 is an orally active pan-RAF inhibitor with IC50s of 3, 6, 10, 15 and 30 nM for LCK, CRAF, SRC, V600E-BRAF and BRAF, respectively. CCT241161 shows good activity to in BRAF and NRAS mutant melanomas. CCT241161 also exhibits anticancer cell proliferative activity[1].
in vivo
CCT241161 (10, 20 mg/kg; i.g; once a day for 7 days) inhibits the growth of BRAF mutant A375, PLX4720-resistant A375 and NRAS mutant DO4 tumor xenografts in mice[1].
| Animal Model: | Female nude mice (5 to 6- week-old)[1]. |
| Dosage: | 10, 20 mg/kg |
| Administration: | Oral gavage; once a day for 7 days. |
| Result: | Showed activity of tumor regression in nude mice with xenografts tumor of BRAF mutant A375, PLX4720-resistant A375 (A375/R) and NRAS mutant DO4, without causing any body weight loss to the mice. |
IC 50
CRAF: 6 nM (IC
50); Braf: 30 nM (IC
50); BRaf
V600E: 15 nM (IC
50); SRC: 0.01 μM (IC
50); LCK: 0.003 μM (IC
50)
References
[1] Girotti MR, et al. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell. 2015 Jan 12;27(1):85-96. DOI:
10.1016/j.ccell.2014.11.006
