Format

Send to

Choose Destination
J Am Chem Soc. 2018 Dec 5;140(48):16428-16432. doi: 10.1021/jacs.8b10320. Epub 2018 Nov 19.

Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion.

Author information

1
Department of Molecular, Cellular and Developmental Biology , Yale University , New Haven , Connecticut 06511 , United States.
2
Arvinas Inc. , New Haven , Connecticut 06511 , United States.
3
Departments of Chemistry and Pharmacology , Yale University , New Haven , Connecticut 06520 , United States.

Abstract

The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention.

PMID:
30427680
DOI:
10.1021/jacs.8b10320

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center