SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases
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Published on: July 25, 2020
Abdelsattar M Omar1,2,3, Maan T Khayat1, Farid Ahmed4,5
1Faculty of Pharmacy, Department of Pharmaceutical Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Tirbanibulin (KX2-391, KX-01), a dual non-ATP (substrate site) Src kinase and tubulin-polymerization inhibitor, demonstrated a universal anti-cancer activity for variety of cancer types. The notion that KX2-391 is a highly selective Src kinase inhibitor have been challenged by recent reports on the activities of this drug against FLT3-ITD mutations in some leukemic cell lines. Therefore, we hypothesized that analogues of KX2-391 may inhibit oncogenic kinases other than Src. A set of 4-aroylaminophenyl-N-benzylacetamides were synthesized and found to be more active against leukemia cell lines compared to solid tumor cell lines. N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (4e) exhibited activities at IC50 0.96 µM, 1.62 µM, 1.90 µM and 4.23 µM against NB4, HL60, MV4-11 and K562 leukemia cell lines, respectively. We found that underlying mechanisms of 4e did not include tubulin polymerization or Src inhibition. Such results interestingly suggested that scaffold-hopping of KX2-391 may change the two main underlying cytotoxic mechanisms (Src and tubulin). Kinase profiling using two methods revealed that 4e significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1/2 (>99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.
Insights
New anticancer compounds, inspired by tirbanibulin, show potent activity against leukemia by inhibiting novel oncogenic kinases like ERK1/2, not Src or tubulin. This discovery highlights diverse therapeutic mechanisms for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Tirbanibulin (KX2-391) is a dual Src kinase and tubulin polymerization inhibitor with broad anticancer activity.
- Recent findings suggest KX2-391 may also affect FLT3-ITD mutations in leukemia, challenging its selectivity.
- This necessitates exploring novel kinase targets beyond Src for anticancer drug development.
Purpose of the Study:
- To synthesize and evaluate novel analogues of KX2-391 for anticancer activity, particularly against leukemia.
- To elucidate the underlying cytotoxic mechanisms of the synthesized compounds.
- To identify new oncogenic kinase targets inhibited by these analogues.
Main Methods:
- Synthesis of a series of 4-aroylaminophenyl-N-benzylacetamides.
- In vitro testing of synthesized compounds against various leukemia and solid tumor cell lines.
- Kinase profiling assays to determine the specific molecular targets and mechanisms of action.
Main Results:
- The compound N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (4e) showed significant activity against multiple leukemia cell lines (IC50 values ranging from 0.96 to 4.23 µM).
- Compound 4e's mechanism of action did not involve Src kinase inhibition or tubulin polymerization.
- Kinase profiling revealed that 4e potently inhibits ERK1/2 and upregulates c-Jun kinase, suggesting novel anticancer pathways.
Conclusions:
- Scaffold-hopping of tirbanibulin can lead to compounds with distinct mechanisms of action, shifting from Src/tubulin inhibition to targeting other oncogenic kinases.
- Compound 4e represents a promising lead for leukemia treatment by targeting novel pathways like ERK1/2.
- Comprehensive kinase profiling is crucial for understanding structure-activity relationships and identifying new therapeutic targets in drug discovery.
