Author: Narla, Rama Krishna ; Peng, Xiaohui ; Fultz, Kimberly E. ; Apuy, Julius ; LeBrun, Laurie ; Bahmanyar, Sogole ; Zhu, Dan ; Cashion, Dan ; Boylan, John F. ; Robinson, Dale ; Elsner, Jan ; Tran, Tam ; Tehrani, Lida ; Leftheris, Katerina ; Riggs, Jennifer R.

TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC₅₀ = 3.0 nM; CAL-51 IC₅₀ = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC₅₀ = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC₅₀ = 3.0 nM; CAL-51 IC₅₀ = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.

01 Aug 2020·Cancer ScienceQ2 · MEDICINE

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Q2 · MEDICINE

ArticleOA

Author: Lei, Zi‐Ning ; Lin, Lizhu ; Zou, Chang ; Wang, Jing‐Quan ; Chen, Zhe‐Sheng ; Teng, Qiu‐Xu ; Yang, Yuqi ; Wu, Zhuo‐Xun ; Wang, Guangsuo ; Sun, Lingling

AbstractOne pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.

09 May 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy

Q1 · MEDICINE

Article

Author: Boylan, John F. ; Fultz, Kimberly E. ; Tran, Tam ; Leftheris, Katerina ; Bahmanyar, Sogole ; Nagy, Mark ; Cashion, Dan ; Peng, Xiaohui ; Kulkarni, Ashutosh ; Riggs, Jennifer R. ; Fenalti, Gustavo ; Zhu, Dan ; Elsner, Jan ; Tehrani, Lida ; Robinson, Dale ; Krishna Narla, Rama ; LeBrun, Laurie ; Condroski, Kevin ; Pagarigan, Barbra

Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	United States	Celgene Corp.	-

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