![]() Trends in kinase drug discovery: targets, indications and inhibitor design. TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway. Gonghua Qi, Hanlin Ma, Yingwei Li, Jiali Peng, Jingying Chen, Beihua Kong.A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation. Mathijssen, Jaap Verweij, Ingmar Bruns, Martijn P. Eder, Martin Gutierrez, Kumar Sankhala, Prabhu Rajagopalan, Isabelle Genvresse, Simon Langer, Ron H.J. Florence Atrafi, Oliver Boix, Vivek Subbiah, Jennifer R.Nature Reviews Molecular Cell Biology 2022, 23 International Journal of Molecular Sciences 2022, 23 Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer. Lauren Pugh, Alisha Pancholi, Priscila Celeste Purat, Sandra Agudo-Alvarez, Raúl Benito-Arenas, Agatha Bastida, Victor M.European Journal of Medicinal Chemistry 2023, 245, 114887. Design, synthesis and biological evaluation of a new class of 7H-pyrrolopyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer. ![]() Xinyue Li, Wei Wei, Longyue Tao, Jun Zeng, Yongxia Zhu, Tianqiong Yang, Qiwei Wang, Minhai Tang, Zhihao Liu, Luoting Yu.Fused Pyridine Derivatives: Synthesis and Biological Activities. Huseyin Istanbullu, Gulsah Bayraktar, Merve Saylam.X-ray Crystal Structure-Guided Design and Optimization of 7H-Pyrrolopyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor. Younho Lee, Hyunkyung Kim, Haelee Kim, Ha Yeon Cho, Jun-Goo Jee, Kyung-Ah Seo, Jung Beom Son, Eunhwa Ko, Hwan Geun Choi, Nam Doo Kim, Ikyon Kim.Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity. Fultz, Rama Krishna Narla, Xiaohui Peng, Tam Tran, Julius Apuy, Laurie LeBrun, Katerina Leftheris, John F. Jan Elsner, Dan Cashion, Dale Robinson, Sogole Bahmanyar, Lida Tehrani, Kimberly E.Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders. Jibu Lu, Yongjun Huang, Jing Huang, Rui He, Minhao Huang, Xiaoyun Lu, Yong Xu, Fengtao Zhou, Zhang Zhang, Ke Ding.Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor. Massirer, Mark Kudolo, Stefan Gerstenecker, Apirat Chaikuad, Lars Zender, Stefan Knapp, Stefan Laufer, Rafael M. Serafim, André da Silva Santiago, Martin P. This article is cited by 15 publications. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models. The imidazopyrazine series displayed more than 10-fold higher potencies however, in the early project phase, this series suffered from poor metabolic stability. The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series “triazolopyridines” and “imidazopyrazines”. Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death.
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