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Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors
Sreekanth A Ramachandran1, Pradeep S Jadhavar1, Sandeep K Miglani1
1Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Abstract:
Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.
Insights
Researchers optimized a novel bis-amide inhibitor targeting colony-stimulating factor 1 receptor (CSF1R) kinase. This potent, orally bioavailable compound shows promise for cancer therapy by modulating tumor-associated macrophages.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Tumor-associated macrophages (TAMs) promote cancer progression via CSF1R signaling.
- Targeting CSF1R is a promising strategy for cancer therapy, with inhibitors in clinical trials.
Purpose of the Study:
- To optimize a lead compound into a potent, orally bioavailable CSF1R inhibitor.
- To improve metabolic stability and cell permeability for enhanced drug properties.
Main Methods:
- Lead optimization of a bis-amide CSF1R inhibitor.
- Utilized docking and biochemical analysis to guide structural modifications.
- Assessed metabolic stability and Caco2 permeability.
Main Results:
- Identified a potent, cellularly active, and orally bioavailable bis-amide CSF1R inhibitor.
- Removed a metabolically labile group, improving drug properties.
- Achieved good oral bioavailability in preclinical models.
Conclusions:
- The optimized bis-amide inhibitor is a promising candidate for cancer treatment.
- Modulating CSF1R signaling via this inhibitor may overcome tumor-promoting macrophage functions.
- Further development could lead to novel cancer therapies.