FRAX597

Biological Activity

In vitro: FRAX597 (100 n M) displays a significant inhibitory capacity toward YES1 (87%), RET (82%), CSF1R (91%), TEK (87%), PAK1 (82%), and PAK2 (93%), while displays minimal inhibitory activity towards the group II PAKs: PAK4 (0%), PAK6 (23%), and PAK7 (8%). FRAX597 treatment dramatically impairs the proliferation of Nf2-null SC4 Schwann cells (SC4 cells). FRAX597 displays an IC50 value of 48 nM against wild type PAK1, while IC 50 values against the V342F and V342Y PAK1 mutants are higher than 3μM and 2 μM, respectively. FRAX597 inhibits the proliferation and motility of both benign (Ben-Men1, 3μM) and malignant (KT21-MG1, 0.4 μM) meningiomas cells after treating of 72 h. In vivo: In NOD/SCID mice which bearing Nf2-/-SC4 Schwann cells, FRAX597 (100 mg/kg/day, p.o.) causes more significant tumor growth inhibition cpmpared with control mice. In SCID mice with orthotopic meningioma, FRAX597 (90 mg/kg/day, p.o.) significantly suppresses tumor growth.In KrasG12D mice, treatment with FRAX597 (90 mg/kg/day, p.o.) causes tumor regression and loss of Erk and Akt activity.

Chemical Information

Molecular Weight	558.10
Formula	C29H28ClN7OS
CAS Number	1286739-19-2
Solubility (25°C)	14 mg/mL warmed in DMSO
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Yeo D, et al. BMC Cancer. FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.

[2] Licciulli S, et al. J Biol Chem. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas.