Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity

Uitdehaag, Joost C.M.; Man, Jos de; Willemsen-Seegers, Nicole; Prinsen, Martine B.W.; Libouban, Marion A.A.; Sterrenburg, Jan Gerard; Wit, Joeri J.P. de; Vetter, Judith R.F. de; Roos, Jeroen A.D.M. de; Buijsman, Rogier C.; Zaman, Guido J.R.

doi:10.1016/j.jmb.2017.05.014

Cited by 45 publications

(74 citation statements)

References 50 publications

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“…S1; Supplementary Table S1A). Compounds 4 and 5 are derivatives of NTRC 0066-0 with increased binding affinity for TTK (33) Supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

TTK Inhibitors as a Targeted Therapy forCTNNB1(β-catenin) Mutant Cancers

Zaman

Roos

Libouban

et al. 2017

Molecular Cancer Therapeutics

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The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for The association of -mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type Treatment of a xenograft model of a -mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high levels. We propose mutant as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials. .

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“…S1; Supplementary Table S1A). Compounds 4 and 5 are derivatives of NTRC 0066-0 with increased binding affinity for TTK (33) Supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

TTK Inhibitors as a Targeted Therapy forCTNNB1(β-catenin) Mutant Cancers

Zaman

Roos

Libouban

et al. 2017

Molecular Cancer Therapeutics

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“…To date, numerous compounds have been developed and patented. Various inhibitors have been shown to exhibit anti-proliferative activity in tumor cells [ 8 , 9 , 10 , 11 ]. The kinase domain of Mps1 adopts a two lobe architecture, including a smaller N-terminal lobe and a larger C-terminal lobe connected by a flexible kinase hinge, and the C604Y mutation is located in the kinase hinge ( Figure 1 A).…”

Section: Introductionmentioning

confidence: 99%

Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study

Chen

Jiang

et al. 2018

Molecules

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Mono-polar spindle 1 (Mps1/TTK) represents a protein kinase reported to be vital for cell division processes and is generally regarded as an attractive target for the treatment of hepatocellular carcinoma, breast carcinoma, and colon cancer. However, the C604Y mutation has been linked to acquired resistance. Recently, three potential small-molecule inhibitors of Mps1 (i.e., reversine, NMS-P715, and its derivative Cpd-5) were reported for the C604Y mutation that exhibit significant resistance to NMS-P715 and Cpd-5, but retain affinity for reversine. In this study, classical molecular dynamic (MD) simulations, accelerated MD (aMD) simulations, and umbrella sampling (US) simulations were performed to illustrate the resistance mechanisms of inhibitors to Mps1. The classical MD simulations combined with free energy calculations revealed that reversine features similar binding affinity characteristics to both Mps1WT and Mps1C604Y, but both NMS-P715 and Cpd-5 feature much higher binding affinities to Mps1WT than to Mps1C604Y. The major variations were shown to be controlled by electrostatic energy and the conformational change of A-loop-induced entropy increased. The large conformational changes of Mps1C604Y bound to NMS-P715 and Cpd-5 were also observed in aMD simulations. The US simulation results further suggest that reversine and Cpd-5 both exhibit similar dissociation processes from both Mps1WT and Mps1C604Y, but Cpd-5 and NMS-P715 were found to dissociate more easily from Mps1C604Y than from Mps1WT, thus a reduced residence time was responsible for the inhibitors resistance to the C604Y mutation. The physical principles provided by the present study may provide important clues for the discovery and rational design of novel inhibitors to combat the C604Y mutation of Mps1.

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“…We showed that the sidechain position of Tyr82 driven by the downward shift of the G-loop is the key determinant for changing the PP1 binding pathway. It has been suggested previously that the downward shift of the G-loop could impact drug efficacy 22 . Also, the sequence alignment data set of 490 kinases 62 ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing experimental evidence that supports the importance of cellular environments for the thermodynamics and kinetics of protein-ligand binding 3,21 . For instance, the efficacy of inhibitors of threonine tyrosine kinases in cells is reduced significantly in many cases compared to that in dilute solution 22 .…”

Section: Introductionmentioning

confidence: 99%

Reduced Efficacy of a Src Kinase Inhibitor in Crowded Protein Solution

Kasahara

Nawrocki

et al. 2020

Preprint

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The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, PP1, in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. Protein functions in a living cell could be examined using atomistic MD simulations with realistic cellular environments.

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Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity

Cited by 45 publications

References 50 publications

TTK Inhibitors as a Targeted Therapy forCTNNB1(β-catenin) Mutant Cancers

TTK Inhibitors as a Targeted Therapy forCTNNB1(β-catenin) Mutant Cancers

Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study

Reduced Efficacy of a Src Kinase Inhibitor in Crowded Protein Solution

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