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Bioorg Med Chem Lett. 2018 Mar 1;28(5):934-941. doi: 10.1016/j.bmcl.2018.01.053. Epub 2018 Feb 9.

Pharmacology and in vivo efficacy of pyridine-pyrimidine amides that inhibit microtubule polymerization.

Author information

1
Frost Biologic, Inc., 5201 South Green St., Suite 160, Salt Lake City, UT 84123, USA; Tolero Pharmaceuticals, Inc., 3900 North Traverse Mountain Blvd., Suite 100, Lehi, UT 84043, USA.
2
Frost Biologic, Inc., 5201 South Green St., Suite 160, Salt Lake City, UT 84123, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
3
Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
4
Frost Biologic, Inc., 5201 South Green St., Suite 160, Salt Lake City, UT 84123, USA; Department of Physiology and Developmental Biology, Brigham Young University, 4005 LSB, Provo, UT 84602, USA. Electronic address: marchansen@byu.edu.

Abstract

Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability. Together with in vivo efficacy models, pharmacology supports further development as a treatment for solid tumors.

KEYWORDS:

Cancer; Microtubule; Tubulin

PMID:
29433928
DOI:
10.1016/j.bmcl.2018.01.053
[Indexed for MEDLINE]

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