Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective Dual FLT3/CDK2 Kinase Inhibitor

• Main Authors: Aya Soudi (Author), Onur Bender (Author), Ismail Celik (Author), Amer Ali Abd El-Hafeez (Author), Rumeysa Dogan (Author), Arzu Atalay (Author), Eslam B. Elkaeed (Author), Aisha A. Alsfouk (Author), Elshimaa M. N. Abdelhafez (Author), Omar M. Aly (Author), Wolfgang Sippl (Author), Taha F. S. Ali (Author)
• Format: Book
• Published: MDPI AG, 2024-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC₅₀ = 2.49 μM) and has demonstrated selectivity towards FLT3 ITD-mutated MV4-11 AML cells, with an IC₅₀ of 4.3 μM. By utilizing the scaffold of the previous hit, sixteen new compounds were synthesized and screened against NCI-60 human cancer cell lines. This leads to the discovery of a potent antiproliferative compound, namely <b>5l</b>, with an average GI₅₀ value against leukemia and colon cancer subpanels equalling 3.39 and 5.97 µM, respectively. Screening against a specific set of 10 kinases that are associated with carcinogenesis indicates that compound <b>5l</b> has a potent FLT3 inhibition (IC₅₀ = 36.21 ± 1.07 nM). Remarkably, compound <b>5l</b> was three times more effective as a CDK2 inhibitor (IC₅₀ = 8.17 ± 0.32 nM) compared to sunitinib (IC₅₀ = 27.90 ± 1.80 nM). Compound <b>5l</b> was further analyzed by means of docking and molecular dynamics simulation for CDK2 and FLT3 active sites which provided a rational for the observed strong inhibition of kinases. These results suggest a novel structural scaffold candidate that simultaneously inhibits CDK2 and FLT3 and gives encouragement for further development as a potential therapeutic for leukemia and colon cancer.

Item Description

10.3390/ph17050659
1424-8247