PD173074 is an ATP-competitive FGFR1 and VEGFR2 inhibitor with an IC50 value of 26nM and 100-200nM, respectively, showing higher selectivity for FGFR1 over PDGFR and c-Src[1]. PD173074 weakly inhibits the activities of Src, InsR, EGFR, PDGFR, MEK, and PKC[2].
in vitro, PD173074 (0.5, 1, 10, 20 and 50μM; 48h) blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells[3]. PD173074 (0.25 or 1µmol/L, 20µL/well; 4h)reverses MRP7 (ABCC10)-mediated multidrug resistance[4]. PD173074 (0-100μM; 30min) binds to the C-terminus of oncofetal architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) and modulates its DNA-binding and transcriptional activation functions[5].
in vivo, PD173074 (50mg/kg; up to 28 days; goral gavage) blocks small cell lung cancer growth in a nude mice model[6]. PD173074 (20 mg/kg; 3 days; i.p)block FGFR-dependent urothelial carcinoma growth in a Balb/c mice model[7]. PD173074 (20mg/kg; once per day; 10 days; i.p) improves antitumor immunity and impairs breast cancer metastasis in a Balb/c mice model[8].
References:
[1] Dimitroff, C J et al. “Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.” *Investigational new drugs* vol. 17,2 (1999): 121-35. doi:10.1023/a:1006367032156
[2] Tan, Li et al. “Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.” *Proceedings of the National Academy of Sciences of the United States of America* vol. 111,45 (2014): E4869-77. doi:10.1073/pnas.1403438111
[3] Qiao, Chuchu et al. “PD173074 blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells.” *PloS one* vol. 15,6 e0234708. 18 Jun. 2020, doi:10.1371/journal.pone.0234708
[4] Anreddy, Nagaraju et al. “PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.” *Acta pharmaceutica Sinica. B* vol. 4,3 (2014): 202-7. doi:10.1016/j.apsb.2014.02.003
[5] Ahmed, Syed Moiz et al. “The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions.” *FEBS letters* vol. 597,15 (2023): 1977-1988. doi:10.1002/1873-3468.14675
[6] Pardo, Olivier E et al. “The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.” *Cancer research*vol. 69,22 (2009): 8645-51. doi:10.1158/0008-5472.CAN-09-1576
[7] Lamont, F R et al. “Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo.” *British journal of cancer* vol. 104,1 (2011): 75-82. doi:10.1038/sj.bjc.6606016
[8] Ye, Tinghong et al. “Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis.” *Breast cancer research and treatment* vol. 143,3 (2014): 435-46. doi:10.1007/s10549-013-2829-y
PD173074是一种ATP竞争性FGFR1和VEGFR2抑制剂，IC50值分别为26nM和100-200nM，对FGFR1的选择性高于PDGFR和c-Src[1]。PD173074抑制Src、InsR、EGFR、PDGFR、MEK和PKC的活性[2]。
在体外，PD173074(0.5、1、10、20、50μM；48h)通过cul3介导的泛素蛋白酶阻断HepG2和Hep3B细胞的G1/S细胞周期转变[3]。PD173074(0.25或1µmol/L； 20µL/孔；4h)逆转MRP7 （ABCC10）介导的多药耐药[4]。PD173074(0 - 100μM；30min)结合到癌胎染色质因子高迁移率组AT-hook 2 (HMGA2)的c端并调节其DNA结合和转录激活功能[5]。
在体内，PD173074 (50mg/kg；最高28天；口服灌胃)在裸鼠模型中阻断小细胞肺癌生长[6]。PD173074 (20mg/kg；3天；腹腔注射）在Balb/c小鼠模型中阻断FGFR依赖性尿路上皮癌生长[7]。PD173074(20毫克/公斤；每天一次；10天；腹腔注射）在Balb/c小鼠模型中提高抗肿瘤免疫，抑制乳腺癌转移[8]。