Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia

  • J Med Chem. 2015 Dec 24;58(24):9625-38. doi: 10.1021/acs.jmedchem.5b01611.
Xixiang Li  1  2 ,  Aoli Wang  1  3 ,  Kailin Yu  1  3 ,  Ziping Qi  1  2 ,  Cheng Chen  1  2 ,  Wenchao Wang  1  2 ,  Chen Hu  1  2 ,  Hong Wu  1  3 ,  Jiaxin Wu  1  3 ,  Zheng Zhao  1  2 ,  Juan Liu  1  2 ,  Fengming Zou  1  2 ,  Li Wang  1  2 ,  Beilei Wang  1  2 ,  Wei Wang  1  2 ,  Shanchun Zhang  2  4 ,  Jing Liu  1  2 ,  Qingsong Liu  1  2  3  5
Affiliations
  • 1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.
  • 2. CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.
  • 3. University of Science and Technology of China , Hefei 230036, Anhui, P. R. China.
  • 4. Hefei Cosource Medicine Technology Co. Ltd., 358 Ganquan Road, Hefei 230031, Anhui, P. R. China.
  • 5. Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031, Anhui, P. R. China.
PMID: 26630553 DOI: 10.1021/acs.jmedchem.5b01611
Abstract

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a Btk kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over Btk kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML Cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-Kit kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-Kit dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced Apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.

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