Author: Elleraas, Jeff ; Tran-Dubé, Michelle ; Salomon-Ferrer, Romelia ; Brun, Sonja ; Gallego, Rebecca A. ; Wang, Fen ; Zou, Aihua ; Bernier, Louise ; Ewanicki, Jason ; Quinlan, Casey L. ; Dress, Klaus ; Johnson, Ted W. ; Wythes, Martin ; Lafontaine, Jennifer ; Toledo, Chad ; VanArsdale, Todd ; Patman, Ryan L. ; Linton, Angelica ; Berry, Madeline ; Li, Jian ; Eisele, Koleen ; Greasley, Samantha ; Fobian, Yvette ; Murtaza, Anwar ; Tran, Phuong ; Wang, Wei ; Khamphavong, Penney ; Miller, Nichol ; Sach, Neal ; Silva, Francisco ; Yang, Shouliang ; Maestre, Michael ; Diehl, Wade ; Greenwald, Eric C. ; McAlpine, Indrawan ; Timofeevski, Sergei ; Auth, Marin ; Chung, Loanne ; Scales, Stephanie ; Richardson, Paul ; Davis, Carl ; Ramms, Dana J.

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

13 Jun 2024·ACS Medicinal Chemistry Letters

Novel 2,7-Naphthyridine Compounds as MASTL Inhibitors for Treating Cancer

Author: Sabnis, Ram W.

Provided herein are novel 2,7-naphthyridine compounds as MASTL inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

01 Aug 2022·Medical Oncology

Therapeutic natural compounds Enzastaurin and Palbociclib inhibit MASTL kinase activity preventing breast cancer cell proliferation

Article

Author: Katiyar, Amit ; Singh, Harpreet ; Rajawat, Jyotika ; Misra, Gauri ; Bhatt, Anant Narayan ; Polisety, Aneesha

Microtubule-associated serine/threonine kinase-like (MASTL) regulates mitotic progression and is an attractive target for the development of new anticancer drugs. In this study, novel inhibitory molecules were screened against MASTL kinase, a protein involved in cell proliferation in breast cancer. Natural source-derived drugs Enzastaurin and Palbociclib were selected to identify their role as MASTL kinase inhibitors. Cytotoxic activity, kinase activity, and other cell-based assays of Enzastaurin and Palbociclib were evaluated on human breast cancer (MCF-7) cells. The potential natural compounds caused cytotoxicity in MCF-7 cells in a dose- and time-dependent manner. Further analysis by Annexin V and PI staining indicated that both drugs are potent inducers of apoptosis. Enzastaurin induced G2/M phase arrest, while Palbociclib caused G1 arrest. MASTL kinase activity was significantly abrogated with both the compounds showing EC₅₀ values of 17.13 µM and 10.51 µM, respectively. Taken together, these data strongly suggest that Enzastaurin and Palbociclib possess the ability to inhibit MASTL kinase activity and induce cell death in breast cancer cells, thus exhibiting significant therapeutic potential.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	Ireland	Pfizer Worldwide Services Unlimited Co.	05 Nov 2024

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