Ponatinib (AP24534)

9号染色体的ABL基因与22号染色体的BCR基因形成BCR-ABL融合基因，BCR-ABL翻译成活性的致癌酪氨酸激酶。根据不同的融合位置形成蛋白变异体，分子量范围介于185至210 kDa之间。BCR-ABL激活JAK / STAT信号通路和MAPK信号[3]。多数慢性粒细胞白血病（CML）、急性淋巴细胞白血病（ALL）和急性骨髓性白血病（AML）病人中都存在该基因。

Ponatinib是BCR-ABL激酶的二代抑制剂，对BCR-ABL突变体（T315I）有效[1,2]，对野生型和突变体的IC50值分别为0.5和11 nM[4]。在Ba / F3细胞系中，Ponatinib也能抑制其他几个临床相关激酶（RET、FLT3、KIT、PDGFRα、PDGFRβ和FGFR1），IC50值分别是5、25、100、5、9和23 nM [4]。

参考文献：
1.Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC (June 2010). Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J. Med. Chem. 53 (12): 4701–19.
2.O'Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moseson EM, Rivera VM, Tang H, Metcalf Ca CA, Bohacek RS, Wang Y, Sundaramoorthi R, Shakespeare WC, Dalgarno D, Clackson T, Sawyer TK, Deininger MW, Druker BJ (2004). Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 104 (8): 2532–2539.
3.Cilloni D and Saglio G. Molecular pathways: BCR-ABL. Clinical Cancer Res (2011) 18(4):930-937
4.?Gozgit JM, Wong MJ, Zhu X, Schrock AB, Chen T, Clackson T and Rivera VM. Ponatinib, a potent pan-BCR-ABL inhibitor, retains activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR α/β and FGFR1. 2012 AACR poster.