The p21-activated kinases (PAKs) have generated significant interest as therapeutic targets in cancer. PAK1 signaling has been shown to be important for regulating cytoskeletal organization and cell migration via both its catalytic activity and protein-protein interactions. FRAX1036, a small molecule pyridopyrimidinone, is a PAK inhibitor. Its biochemical potency (Ki) against PAK1 and PAK2 is 23.3 and 72.4 nM, respectively, with high selectivity against PAK4. Potent cellular inhibition of group I PAK substrate phosphorylation was observed at 2.5 to 5 μM concentrations of FRAX1036 in PAK1-amplified MDA-MB-175 cells. FRAX1036 (5 μM) and docetaxel (0.2 μM) combination treatment for 24 hours of PAK1-amplified lines, MDA-MB-175 and HCC2911, elevated a major apoptotic marker (cleaved PARP) and attenuated a cell cycle regulator (cyclin D1). After 20 hours of treatment with 2.5 μM FRAX1036 for 20 hours, microtubules were disorganized and were not evenly distributed throughout the cytoplasm, between the microtubule organizing center and the periphery. Furthermore, FRAX1036-treated cells completed normal mitoses with the majority of apoptosis occurring during interphase (66.7%)[3].
FRAX1036 细胞实验
Cell Line
Concentration
Treated Time
Description
References
8505C
>10 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
SW1736
>10 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
HTh74
6.14 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
BCPAP
7.73 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
TPC1
3.94 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
K1
>10 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
THJ-16T
>10 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
FTC133
>10 μM
72 hours
Reduced thyroid cancer cell viability
Endocr Relat Cancer. 2019 Aug;26(8):699-712.
U2OS
2.5 μM FRAX1036, 0.2 μM docetaxel
20 hours
To evaluate the effect of FRAX1036 and docetaxel on microtubule organization and cell fate, disorganized microtubules and increased apoptosis were observed.
Breast Cancer Res. 2015 Apr 23;17(1):59.
HCC2911
5 μM FRAX1036, 0.2 μM docetaxel
24 hours
To evaluate the effect of FRAX1036 and docetaxel combination on apoptosis, increased apoptotic markers (cleaved PARP) and decreased cell cycle regulators (cyclin D1) were observed.
Breast Cancer Res. 2015 Apr 23;17(1):59.
MDA-MB-175
0.5, 1, 2.5, 5 μM
24 hours
To evaluate the effect of FRAX1036 on PAK1 effector signaling and cell survival, inhibition of PAK1 effector signaling (MEK1-S298 and CRAF-S338) was observed to correlate with PARP cleavage.
Breast Cancer Res. 2015 Apr 23;17(1):59.
SW480
3 μM
25 days
To evaluate the effect of FRAX1036 on SW480 cell proliferation, results showed that SW480 cells regrew after 25 days of prolonged exposure to FRAX1036.
Br J Cancer. 2023 Oct;129(7):1071-1082.
HCT116
1 μM
21 days
To evaluate the effect of FRAX1036 on HCT116 cell proliferation, results showed that HCT116 cells regrew after 21 days of prolonged exposure to FRAX1036.
Br J Cancer. 2023 Oct;129(7):1071-1082.
T47D
IC50 5.0–11.5 µM
72 hours
Evaluate the anti-proliferative effect of FRAX1036 in T47D cells, showing lower activity in luminal cell lines.
Breast Cancer Res Treat. 2019 Sep;177(2):369-382.
BT474
IC50 5.0–11.5 µM
72 hours
Evaluate the anti-proliferative effect of FRAX1036 in BT474 cells, showing lower activity in luminal cell lines.
Breast Cancer Res Treat. 2019 Sep;177(2):369-382.
MCF7
IC50 5.0–11.5 µM
72 hours
Evaluate the anti-proliferative effect of FRAX1036 in MCF7 cells, showing lower activity in luminal cell lines.
Breast Cancer Res Treat. 2019 Sep;177(2):369-382.
A549 cells
10 μM
24-48 hours
To evaluate the effect of FRAX1036 on the morphology, motility, and proliferation of A549 cells. Results showed that FRAX1036 combined with prenylation inhibitors significantly altered cell morphology and motility, and reduced cell proliferation.
BMC Cancer. 2015 May 9;15:381.
H157 cells
10 μM
24-48 hours
To evaluate the effect of FRAX1036 on the morphology, motility, and proliferation of H157 cells. Results showed that FRAX1036 combined with prenylation inhibitors significantly altered cell morphology and motility, and reduced cell proliferation.
BMC Cancer. 2015 May 9;15:381.
Madin-Darby canine kidney cells (MDCK)
10 μM
60 minutes
Evaluated permeability with Papp value of 1.2×10−6 cm/s
ACS Med Chem Lett. 2015 Oct 31;6(12):1241-6.
MS02 cells
0.6 μM, 1.2 μM, 2.5 μM, 5.0 μM
2 hours
To evaluate the inhibitory effect of FRAX-1036 on PAK1 phosphorylation, results showed a profound inhibitory effect on PAK1 autophosphorylation.
Hum Mol Genet. 2021 Aug 12;30(17):1607-1617.
FRAX1036 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
MPNST subcutaneous xenograft model
Oral
30 mg/kg/day
Once daily for 4 weeks
To evaluate the inhibitory effect of Frax1036 alone or in combination with MEK1/2 inhibitor PD-901 on MPNST xenograft growth, results showed the combination therapy significantly inhibited tumor growth
Oncogene. 2017 Sep 21;36(38):5421-5431
NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice
BT474 orthotopic xenografts
Oral gavage
20 mg/kg daily
Daily for 21 days
Evaluate the anti-tumor effect of FRAX1036 in BT474 xenograft model, showing significant tumor growth inhibition when combined with alisertib.
Breast Cancer Res Treat. 2019 Sep;177(2):369-382.
Mice
H292 NSCLC xenograft model
Oral
10, 20, 30 mg/kg
Single dose, samples collected 6 hours post-dose
Assessed inhibition of pharmacodynamic biomarker pMEK S298, showing dose-dependent suppression
ACS Med Chem Lett. 2015 Oct 31;6(12):1241-6.
Mice
Nf2 conditional knockout mouse model
Oral gavage
30 mg/kg
Once daily for 12 weeks
To evaluate the efficacy of FRAX-1036 in slowing the growth of established schwannomas, results showed insignificant efficacy in vivo.
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