Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase
Arunkranthi Maturi1, Kasinathuni Naga Visweswara Sastry1, Surendra Kumar1
1Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea.
Abstract:
Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations. Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein-ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC50 up to < 0.5 nM for diverse RET alterations.
Insights
Researchers developed novel imidazopyridazine compounds targeting RET kinase alterations. These compounds show high potency against diverse RET alterations, offering potential for improved cancer therapeutics.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Actionable RET kinase mutations drive various solid tumors like thyroid, colorectal, and lung cancers.
- Current RET inhibitors face challenges including acquired resistance and limited response rates.
Purpose of the Study:
- To investigate novel imidazopyridazine compounds as tool compounds for studying RET alterations.
- To design next-generation RET inhibitors overcoming drug resistance and improving clinical efficacy.
Main Methods:
- Synthesized imidazopyridazine derivatives with modifications at specific positions.
- Evaluated inhibitory activity against diverse RET alterations, determining IC50 values.
Main Results:
- Compounds demonstrated potent inhibition of RET alterations, with IC50 values < 0.5 nM.
- Modifications to side chains at the second and sixth positions significantly enhanced potency.
Conclusions:
- Novel imidazopyridazine compounds show promise as potent inhibitors for RET-driven cancers.
- These tool compounds can aid in understanding resistance mechanisms and developing advanced therapeutics.
