Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Abstract

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 μM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

• Authors: Shih-Hsien Chuang, Ying-Shuan E Lee, Lynn Y L Huang, Chi-Kuan Chen, Chun-Liang Lai, Yu-Hsiang Lin, Ju-Ying Yang, Sheng-Chuan Yang, Lien-Hsiang Chang, Ching-Hui Chen, Chia-Wei Liu, Her-Sheng Lin, Yi-Ru Lee, Kuan Pin Huang, Kuo Chu Fu, Hsueh-Min Jen, Jun-Yu Lai, Pei-Shiou Jian, Yu-Chuan Wang, Wen-Yun Hsueh, Pei-Yi Tsai, Wan-Hua Hong, Chia-Chi Chang, Diana Zc Wu, Jinn Wu, Meng-Hsin Chen, Kuo-Ming Yu, Ching Yuh Chern, Jia-Ming Chang, Johnson Y N Lau, Jiann-Jyh Huang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 191 Pg. 112118 (Apr 01 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32113126 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cytoskeletal Proteins
• NDC80 protein, human
• Protein Kinase Inhibitors
• NEK2 protein, human
• NIMA-Related Kinases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytoskeletal Proteins (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• K562 Cells
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, SCID
• Molecular Docking Simulation
• Molecular Structure
• NIMA-Related Kinases (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tissue Distribution