SMI-4a

SMI-4a是PIM1的选择性抑制剂，IC 50值为17 nM[1,2]。

PIM-1是由人PIM1基因编码的酶。研究表明，PIM-1直接参与细胞周期和凋亡进程，在实体癌和恶性血液病中，PIM激酶的过表达可促进细胞生长和存活[3,4]。
SMI-4a是PIM激酶的选择性抑制剂，相较于SMI-16a具有更强的活性。在人红白血病细胞系K562中，SIM-4a通过抑制PIM的活性，进而抑制mTORC1的活性，参与调节细胞生长和激活AMPK [5]。在25白血病细胞系中，SMI-4a诱导细胞周期停滞，促进细胞凋亡。在淋巴母细胞淋巴瘤T-LBL/ T-ALL中，SMI-4a通过线粒体途径和抑制mTORC1发挥较高的选择性 [2]。

在使用2 × 106 6812/2细胞进行皮下异种移植的Nu/nu裸鼠模型中，从第三天口服SMI-4a，每天两次，每周5 -7天，直至第21天肿瘤体积显著下降[2]。

参考文献：
[1].Beharry, Z., et al., Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells. Mol Cancer Ther, 2009. 8(6): p. 1473-83.
[2].Lin, Y.W., et al., A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood, 2010. 115(4): p. 824-33.
[3].Liu, Z., et al., Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer. Oncotarget, 2015.
[4].Warfel, N.A. and A.S. Kraft, PIM kinase (and Akt) biology and signaling in tumors. Pharmacol Ther, 2015.
[5].Beharry, Z., et al., The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci U S A, 2011. 108(2): p. 528-33.