CCT241161

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].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Src

Signaling Pathways >> MAPK/ERK Pathway >> Raf

CRAF:6 nM (IC50)

Braf:30 nM (IC50)

BRafV600E:15 nM (IC50)

SRC:0.01 μM (IC50)

LCK:0.003 μM (IC50)

CCT241161 (1, 3, 10, 30, 100 nM; 24 h) inhibits MEK and ERK in WM266.4 cells[1]. CCT241161 (1, 10, 100 nM and 1, 10, 100 µM) inhibits BRAFV600E in Ba/F3 cells[1]. CCT241161 (0.5 µM; 20 days) inhibits A375 cell but not cause drug resistance[1]. CCT241161 (1 µM , 4 h) inhibits BRAF-inhibitor-resistant melanoma cells[1]. CCT241161 (0.1, 0.3, 1, 3, 10 µM; 24 h) inhibits MEK in NRAS mutant cells[1]. CCT241161 (0.1, 1, 10, 100 µM) shows anti-proliferative activity in D04 cells[1]. Cell Viability Assay[1] Cell Line: WM266.4 cells (BRAF mutant) Concentration: 1, 3, 10, 30, 100 nM Incubation Time: 24 h Result: Exhibited effects of inhibiting MEK and ERK in WM266.4 cells. Cell Viability Assay[1] Cell Line: Ba/F3 cells Concentration: 1, 10, 100 nM and 1, 10, 100 µM Incubation Time: Result: Inhibited BRAF-V600E and BRAF-T529N, V600E in Ba/F3 cells. Cell Viability Assay[1] Cell Line: A375 cell Concentration: 0.5 µM Incubation Time: 20 days Result: Maintained inhibitory activity against A375 cell ,without drug resistance in 20 days. Cell Proliferation Assay[1] Cell Line: D04 cells Concentration: 0.1, 1, 10, 100 µM Incubation Time: Result: Efficiently inhibited NRAS mutant cell growth. Western Blot Analysis[1] Cell Line: patient #2 (PLX4720-resistant cells from patient with vemurafenib-resistant melanoma) Concentration: 1 µM Incubation Time: 4 h Result: Inhibited MEK, ERK, and SRC in the cells from patient #2. Western Blot Analysis[1] Cell Line: D04 cells Concentration: 0.1, 0.3, 1, 3, 10 µM Incubation Time: 24 h Result: Showed activity of surpressing MEK in NRAS mutant cells.

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.

[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.