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Mixed Lineage Kinase Suppression in Triple-Negative Breast Cancer: Identification of a Dual Inhibitor Targeting MLK3
Ganga Reddy Velma1, Sandeep Kumar2,3, Piush Srivastava2
1Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
Abstract:
Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapeutic options. Mixed lineage kinase 3 (MLK3) plays a key role in TNBC progression. To enhance the therapeutic impact of MLK3 inhibition in TNBC, a novel MLK3 inhibitor scaffold was optimized to incorporate inhibition of NAMPT, often upregulated in TNBC to meet the increased demand for NAD+. Cell-free and cell-based assays for MLK3 and NAMPT inhibition drove the design and optimization of GR2-128, a dual inhibitor with matched nanomolar inhibition for MLK3 and NAMPT, antiproliferative in TNBC cell lines, with acceptable metabolic stability and bioavailability. GR2-128 attenuated tumorigenesis in a syngeneic mouse breast cancer model, increasing apoptosis via inhibition of MLK3 and NAMPT, attenuating macrophage and neutrophil infiltration and increasing tumor T-cell markers without change in B-cell count. These data support the dual inhibition of MLK3/NAMPT as a therapeutic approach to TNBC, with the potential for tumor immuno-sensitization.
Insights
A new dual inhibitor, GR2-128, targets both MLK3 and NAMPT, offering a novel therapeutic strategy for triple-negative breast cancer (TNBC). This approach shows promise in reducing tumor growth and sensitizing tumors to immune responses.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- Mixed lineage kinase 3 (MLK3) is implicated in TNBC progression.
- Nicotinamide phosphoribosyltransferase (NAMPT) is upregulated in TNBC to meet NAD+ demands.
Purpose of the Study:
- To develop a novel dual inhibitor targeting both MLK3 and NAMPT for enhanced TNBC therapy.
- To evaluate the efficacy and immunomodulatory effects of the dual inhibitor GR2-128.
Main Methods:
- Design and optimization of GR2-128 using cell-free and cell-based assays.
- Assessment of GR2-128's antiproliferative activity in TNBC cell lines.
- In vivo studies in a syngeneic mouse breast cancer model.
Main Results:
- GR2-128 demonstrated matched nanomolar inhibition of MLK3 and NAMPT.
- GR2-128 exhibited antiproliferative effects in TNBC cell lines with favorable pharmacokinetics.
- In vivo, GR2-128 reduced tumor growth, increased apoptosis, modulated immune cell infiltration, and enhanced tumor T-cell markers.
Conclusions:
- Dual inhibition of MLK3 and NAMPT is a viable therapeutic strategy for TNBC.
- GR2-128 shows potential for TNBC treatment and tumor immuno-sensitization.
