Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT

Jaideep B. Bharate, Nicholas McConnell, Gunaganti Naresh, Lingtian Zhang, Naga Rajiv Lakkaniga, Lucky Ding, Neil P. Shah, Brendan Frett, Hong Yu Li

Research output: Contribution to journalArticle

Abstract

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

Original languageEnglish (US)
Article number3722
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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Diamines
Protein-Tyrosine Kinases
Acute Myeloid Leukemia
Phosphotransferases
pyrimidine
Drug Discovery
Inhibitory Concentration 50
Cell Line

ASJC Scopus subject areas

  • General

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Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT. / Bharate, Jaideep B.; McConnell, Nicholas; Naresh, Gunaganti; Zhang, Lingtian; Lakkaniga, Naga Rajiv; Ding, Lucky; Shah, Neil P.; Frett, Brendan; Li, Hong Yu.

In: Scientific Reports, Vol. 8, No. 1, 3722, 01.12.2018.

Research output: Contribution to journalArticle

Bharate, Jaideep B. ; McConnell, Nicholas ; Naresh, Gunaganti ; Zhang, Lingtian ; Lakkaniga, Naga Rajiv ; Ding, Lucky ; Shah, Neil P. ; Frett, Brendan ; Li, Hong Yu. / Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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