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

  • J Med Chem. 2026 Jun 25;69(12):14191-14212. doi: 10.1021/acs.jmedchem.5c03558.
Ganga Reddy Velma  1 ,  Sandeep Kumar  2  3 ,  Piush Srivastava  2 ,  Sweta Misra  4 ,  Rakesh Sathish Nair  2 ,  Soumya Reddy Musku  1 ,  Martha Ackerman-Berrier  1 ,  Sunil Kumar Singh  2 ,  Harsh Vyas  2 ,  Erick T M Alves  1 ,  Basabi Rana  2  3  5 ,  Rui Xiong  4 ,  Laura Bloem  4 ,  Ajay Rana  2  3  5 ,  Gregory R J Thatcher  1
Affiliations
  • 1. Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • 2. Department of Surgery, Division of Surgical Oncology, The University of Illinois Chicago, Chicago, Illinois 60612, United States.
  • 3. University of Illinois Hospital & Health Sciences System Cancer Center, The University of Illinois Chicago, Chicago, Illinois 60612, United States.
  • 4. UICentre for Drug Discovery, The University of Illinois Chicago, Chicago, Illinois 60612, United States.
  • 5. Jesse Brown VA Medical Center, Chicago, Illinois 60612, United States.
PMID: 42269602 DOI: 10.1021/acs.jmedchem.5c03558
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.

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