Design and Synthesis of Selective FLT3 Inhibitors Via Exploration of Back Pocket II

Abstract

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC₅₀: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

Graphical Abstract

Keywords: :

• acute myeloid leukemia
• bioinformatics
• FLT3
• modeling
• selectivity
• small molecular inhibitors
• structure-based

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Author contributions

QX Wang: synthesis, computational, data curation, writing – original draft; YH Cao: synthesis, writing – original draft; LJ Yang: synthesis, writing – original draft; JZ Wu: synthesis, data curation, revision; ZJ Tong: synthesis, data curation, revision; YY Ma: investigation, data curation, writing – original draft; N Li: synthesis, writing – original draft; SH Wu: investigation; L Chen: BioTest, data curation; XL Wang: investigation, formal analysis; X Xue: supervision – BioTest; N Ding: formal analysis; XJ Leng: supervision – BioTest; L Chang: supervision – synthesis, funding acquisition; WC Dai: investigation; YC Yu: formal analysis; SL Sun: supervision – computational, writing – review and editing, funding acquisition; Y Yang: supervision, writing – review and editing; NG Li: supervision, writing – review and editing, funding acquisition; ZH Shi: supervision, writing – review and editing

Financial & competing interests disclosure

This work was financially supported by National Natural Science Foundation of China (81502986, 81973171, 82103985 and 82103987); Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX20_1561, SJCX20_0533); project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions; project funded by the Flagship Major Development of Jiangsu Higher Education Institutions (PPZY2015A070); Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization (ZDXM-2020-19); National Key Research and Development Program of China (2020YFA0509404); Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine (2020YLXK002); Key Laboratory of Therapeutic Material of Chinese Medicine, Jiangsu Province; and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.