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Discovery and Biological Evaluation of Novel, Potent, and Orally Available CBLB Inhibitors
Fanye Meng1, Zhongying Cao1, Jinxin Liu1
1Insilico Medicine Shanghai Ltd, Suite 902, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
Abstract:
Casitas B-lineage lymphoma-b (CBLB) has emerged as a promising therapeutic target for cancer immunotherapy due to its central role in modulating T-cell activation and immune tolerance. In this work, we employed a structure-guided drug discovery approach, leveraging the cocrystal structure of CBLB with the hit compound to systematically optimize potency, selectivity, and pharmacokinetic profiles. Through iterative structure-activity relationship (SAR) exploration, we identified compound 10, which is a potent and orally bioavailable CBLB inhibitor with favorable ADME properties. In vivo studies demonstrated that compound 10 exhibits significant antitumor efficacy in syngeneic mouse models, synergizes strongly with anti-PD-1 therapy to enhance tumor regression, and induces durable immune memory against tumor rechallenge. Comprehensive PK/PD analyses revealed sustained target engagement and dose-dependent modulation of downstream biomarkers. Our detailed SAR elucidation provides a roadmap for further optimization of CBLB inhibitors.
Insights
Casitas B-lineage lymphoma-b (CBLB) is a key target in cancer immunotherapy. A novel CBLB inhibitor, compound 10, shows potent antitumor effects and enhances anti-PD-1 therapy by improving T-cell activation.
Area of Science:
- Immunology
- Pharmacology
- Drug Discovery
Background:
- Casitas B-lineage lymphoma-b (CBLB) plays a crucial role in T-cell activation and immune tolerance, making it a significant target for cancer immunotherapy.
- Modulating CBLB activity offers a potential strategy to overcome immune suppression in the tumor microenvironment.
Purpose of the Study:
- To identify and optimize novel inhibitors of CBLB using a structure-guided drug discovery approach.
- To evaluate the in vivo efficacy and therapeutic potential of a lead CBLB inhibitor in combination with existing cancer therapies.
Main Methods:
- Utilized a structure-guided drug discovery strategy based on the cocrystal structure of CBLB.
- Conducted iterative structure-activity relationship (SAR) studies to optimize compound properties.
- Performed in vivo studies in syngeneic mouse models to assess antitumor efficacy and combination effects.
- Carried out pharmacokinetic/pharmacodynamic (PK/PD) analyses to understand target engagement and biomarker modulation.
Main Results:
- Identified compound 10, a potent, orally bioavailable CBLB inhibitor with favorable ADME properties.
- Demonstrated significant antitumor efficacy of compound 10 in syngeneic mouse models.
- Showcased strong synergy between compound 10 and anti-PD-1 therapy, leading to enhanced tumor regression.
- Observed induction of durable immune memory and dose-dependent modulation of downstream biomarkers.
Conclusions:
- Compound 10 represents a promising therapeutic candidate for cancer immunotherapy, effectively inhibiting CBLB and enhancing anti-PD-1 treatment.
- The detailed SAR elucidation provides a valuable framework for the future development of optimized CBLB inhibitors.
- Targeting CBLB holds significant potential for improving cancer treatment outcomes by restoring T-cell function and overcoming immune tolerance.
