Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors

Autor: La Pietra, Valeria, Sartini, Stefania, Botta, Lorenzo, Antonelli, Alessandro, Ferrari, Silvia Martina, Fallahi, Poupak, Moriconi, Alessio, Coviello, Vito, Quattrini, Luca, Yi-Yu, Ke, Hsing-Pang, Hsieh, Da Settimo, Federico, Novellino, Ettore, La Motta, Concettina, Marinelli, Luciana
Přispěvatelé: La Pietra, Valeria, Sartini, Stefania, Botta, Lorenzo, Antonelli, Alessandro, Ferrari, Silvia Martina, Fallahi, Poupak, Moriconi, Alessio, Coviello, Vito, Quattrini, Luca, Ke, Yi-Yu, Hsing-Pang, Hsieh, Da Settimo, Federico, Novellino, Ettore, La Motta, Concettina, Marinelli, Luciana
Rok vydání: 2017
Předmět:
0301 basic medicine
endocrine system diseases
RET kinase
Thyroid Gland
Drug Screening Assays
Settore CHIM/06
Docking
0302 clinical medicine
Drug Discovery
Medullary thyroid carcinoma
Receptor
Tumor
Molecular Structure
Kinase
Chemistry
Thyroid
Medullary thyroid cancer
General Medicine
Neuroendocrine
medicine.anatomical_structure
030220 oncology & carcinogenesis
Focused library
Virtual screening
Pharmacology
Drug Discovery3003 Pharmaceutical Science
Organic Chemistry
Drug
endocrine system
Antineoplastic Agents
Carcinoma
Neuroendocrine
Cell Line
Tumor
Cell Proliferation
Dose-Response Relationship
Drug
Drug Screening Assays
Antitumor
Humans
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ret
Structure-Activity Relationship
Thyroid Neoplasms
Cell Line
Dose-Response Relationship
Thyroid carcinoma
03 medical and health sciences
medicine
Carcinoma
Wild type
Antitumor
medicine.disease
030104 developmental biology
Protein kinase domain
Cell culture
Cancer research
Zdroj: European journal of medicinal chemistry. 150
ISSN: 1768-3254
Popis: It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.
Databáze: OpenAIRE
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