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Published on: January 22, 2019
Synthesis, and evaluation of novel low nanomolar isoindigo-based RET kinase inhibitors
Mazen Al Sulaibi1, Hamdi Nsairat1, Jalal Zahra2
1Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University Amman 19328 Jordan h.alnseirat@ammanu.edu.jo.
Abstract:
Acquired resistance to selective kinase inhibitors remains a primary challenge in targeted cancer therapy. The clinical efficacy of potent rearranged during transfection (RET) inhibitors, for instance, is often attenuated by the emergence of on-target mutations, such as the V804L gatekeeper variant. To address this, a novel series of isoindigo-based compounds were designed, synthesized, and evaluated for RET kinase inhibitory activity. This effort led to the identification of compound 4c, which demonstrated potent, low-nanomolar inhibition of wild-type RET kinase (IC50 = 13.7 nM) and retained, even enhanced, biochemical potency against the clinically relevant RET V804L gatekeeper mutant (IC50 = 5.2 nM). Kinase selectivity profiling confirmed that 4c displays a favorable selectivity profile, with negligible activity against c-KIT, a common off-target associated with toxicity in less selective multi-kinase inhibitors. Molecular modelling provided a structural rationale for the enhanced potency against the V804L mutant. These findings identify compound 4c as an early lead with promising biochemical potency in this initial exploration of isoindigo-based RET inhibitors. However, it should be noted that these results are based on biochemical (enzymatic) assays only, and further cell-based validation is required to assess the translational potential of this compound.
Insights
A new isoindigo-based compound, 4c, shows potent inhibition against rearranged during transfection (RET) kinase. It effectively targets wild-type RET and the V804L gatekeeper mutation, offering a promising strategy for overcoming drug resistance in cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Acquired resistance to kinase inhibitors is a major hurdle in targeted cancer therapy.
- On-target mutations, like the V804L gatekeeper variant in rearranged during transfection (RET) kinase, often cause resistance to existing inhibitors.
- Developing novel inhibitors that overcome these resistance mechanisms is crucial.
Purpose of the Study:
- To design, synthesize, and evaluate a novel series of isoindigo-based compounds for RET kinase inhibitory activity.
- To identify compounds effective against both wild-type RET and clinically relevant resistant mutants.
- To explore the potential of isoindigo derivatives as next-generation RET inhibitors.
Main Methods:
- Synthesis of a novel series of isoindigo-based compounds.
- Biochemical (enzymatic) assays to determine inhibitory activity (IC50 values) against wild-type RET and RET V804L mutant.
- Kinase selectivity profiling to assess off-target activity.
- Molecular modelling to understand the structural basis of inhibition.
Main Results:
- Compound 4c demonstrated potent low-nanomolar inhibition of wild-type RET kinase (IC50 = 13.7 nM).
- Compound 4c retained and even enhanced potency against the RET V804L gatekeeper mutant (IC50 = 5.2 nM).
- 4c exhibited favorable selectivity, with negligible activity against c-KIT, and molecular modelling provided a structural rationale for its enhanced potency against the V804L mutant.
Conclusions:
- Compound 4c is identified as an early lead isoindigo-based RET inhibitor with promising biochemical potency.
- The compound shows potential for overcoming resistance mediated by the RET V804L gatekeeper mutation.
- Further cell-based validation is necessary to confirm the translational potential of compound 4c in cancer therapy.
