Mixed Lineage Kinase Suppression in Triple-Negative Breast Cancer: Identification of a Dual Inhibitor Targeting MLK3 and NAMPT

2026-06-10

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Velma Ganga Reddy

Sandeep Kumar

Piush Srivastava

Sweta Misra

Rakesh Sathish Nair

Soumya Reddy Musku

Martha Ackerman-Berrier

Sunil Kumar Singh

Harsh Vyas

Erick T. M. Alves

Basabi Rana

Rui Xiong

Laura Bloem

Ajay Rana *

Gregory R. J. Thatcher *

DOI：10.1021/acs.jmedchem.5c03558

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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.

Keywords:

Cancer

Inhibition

Inhibitors

Peptides and proteins

Rodent models

Mixed Lineage Kinase Suppression in Triple-Negative Breast Cancer: Identification of a Dual Inhibitor Targeting MLK3 and NAMPT

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