Cancer is the second leading cause of death in United States and new therapeutics are desperately needed to combat the disease. In 1985, the RET (RE-arranged during Transfection) gene was identified as a novel oncogene activated through chromosomal rearrangement. Since then, RET has been identified as a driving oncogene in several cancers, especially for medullary thyroid cancer (MTC). Due to the challenges of identifying a selective RET inhibitor, a treatment for MTC is still an unmet medical need. In an effort to develop a RET kinase inhibitor, a picomolar RET/VEGFR2 clinical candidate has been developed and is currently in preclinical studies. However, the inhibition of VEGFR2 is associated with vascular on-target dose-limiting toxicities, including hypertension in patients for most VEGFR2 inhibitor drugs. We wish to further develop an inhibitor by removing VEGFR2 activity and improving overall selectivity in the kinome, thereby achieving maximal/or complete inhibition of the RET-signaling pathway in patients. We will utilize validated computational models of RET and VEGFR2, fragment-based screening, and potential X-ray crystal structural information to develop a clinical candidate with >30 times RET selectivity over VEGFR2. The resulting selective RET inhibitor could maximally block the RET signaling pathway and will increase MTC survival from months to multiple years.

Public Health Relevance

Cancer is the second leading cause of death in United States, and new therapeutics are desperately needed to combat this disease. Due to the challenges of identifying a selective RET inhibitor, an effective treatment of medullary thyroid cancer (MTC) is still an unmet medical need. In a new research effort we will utilize validated computational models of RET and fragment-based screening to develop a RET inhibitor clinical candidate with a high kinase selectivity profile. The resulting selective RET inhibitor is expected to increase MTC survival from months to multiple years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197178-05
Application #
9763513
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Forry, Suzanne L
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
Schools of Pharmacy
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Zhang, Ya-Jun; Xu, Zhi-Gang; Li, Shi-Qiang et al. (2018) Benzimidazoisoquinoline derivatives inhibit glioblastoma cell proliferation through down-regulating Raf/MEK/ERK and PI3K/AKT pathways. Cancer Cell Int 18:90
He, Liu-Jun; Yang, Dong-Lin; Li, Shi-Qiang et al. (2018) Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. Bioorg Med Chem 26:3899-3908
Parascandolo, Alessia; Laukkanen, Mikko O; De Rosa, Nancy et al. (2018) A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma. Oncotarget 9:4496-4510
Nakaoku, Takashi; Kohno, Takashi; Araki, Mitsugu et al. (2018) A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun 9:625
Gunaganti, Naresh; Kharbanda, Anupreet; Lakkaniga, Naga Rajiv et al. (2018) Catalyst free, C-3 functionalization of imidazo[1,2-a]pyridines to rapidly access new chemical space for drug discovery efforts. Chem Commun (Camb) 54:12954-12957
Frett, Brendan; McConnell, Nicholas; Kharbanda, Anupreet et al. (2018) Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives. Tetrahedron 74:4592-4600
Xu, Zhi-Gang; Li, Shi-Qiang; Meng, Jiang-Ping et al. (2018) Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction. Chemistry 24:6732-6736
Plenker, Dennis; Riedel, Maximilian; Br├Ągelmann, Johannes et al. (2017) Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med 9:
McConnell, Nicholas; Xu, Zhigang; Kumarasamy, Vishnu et al. (2017) Synthesis of Constrained Heterocycles Employing Two Post-Ugi Cyclization Methods for Rapid Library Generation with In Cellulo Activity. ChemistrySelect 2:11821-11825
De Falco, Valentina; Carlomagno, Francesca; Li, Hong-Yu et al. (2017) The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer. Best Pract Res Clin Endocrinol Metab 31:307-318

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