Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

Wéber, Csaba; Sipos, Melinda; Paczal, Attila; Balint, Balázs; Kun, Vilibald; Foloppe, Nicolas; Dokurno, P.; Massey, Andrew; Walmsley, Lee; Hubbard, Roderick E.; Murray, James B.; Benwell, Karen; Edmonds, Thomas; Demarles, Didier; Bruno, Alain; Burbridge, Mike F.; Cruzalegui, Francisco; Kotschy, András

doi:10.1021/acs.jmedchem.1c00023

Cited by 27 publications

(26 citation statements)

References 32 publications

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“…4b ). The occupancy of the ATP-binding pocket is the same with all reported co-crystal structures 31 , 32 , 46 – 48 . The benzothiazole and pyrimidine rings were located deep into the ATP binding site.…”

Section: Resultssupporting

confidence: 76%

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer

Yuan

Kuang

et al. 2022

Nat Commun

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Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.

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Section: Resultssupporting

confidence: 76%

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer

Yuan

Kuang

et al. 2022

Nat Commun

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“…The optimization of fragment 3 with a similar binding mode to harmine is described in a separate publication. 32 The fragment 1 (Figure 2b) makes a "classical" set of hydrogen bonds with the hinge, overlapping with the core of 10 which also interacts with E203 through the NH 2 of the pendant amino pyrimidine (Figure 2b). Fragment 5 (Figure 2c) was selected for further study as it makes a comprehensive set of interactions not only with the hinge but also with the catalytic residues at the base of the binding site through a well-defined network of hydrogen bonds to water.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Here, we describe the initial fragment-based hit discovery efforts that identified multiple series of hit compounds and the lead optimization aided by molecular modeling that generated pyrrolopyrimidine compounds that were profiled in several cellular and in vivo models. An accompanying paper 32 describes a companion optimization project to generate imidazopyridine compounds that were similarly profiled. DYRK1A and DYRK1B vary by only one amino acid in the ATP-binding pocket; the Class 2 DYRKs have more variation.…”

Section: ■ Introductionmentioning

confidence: 99%

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Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

et al. 2021

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The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

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“…Therefore, considerable attempts are focused on the discovery of novel potent and selective DYRK1A inhibitors, which has been accelerated through the method of structure and fragment-based drug design [ 9 ]. For example, imidazopyridine [ 10 ] and pyrrolopyrimidine compounds [ 11 ] were identified as potent and selective DYRK1A inhibitors using fragment-based hit discovery and structure-based optimization strategy. Harmine derivatives were also optimized as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer’s disease [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models

Guan

Fan

et al. 2022

Molecules

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Dual-specific tyrosine phosphorylation regulated kinase 1 (DYRK1A) has been regarded as a potential therapeutic target of neurodegenerative diseases, and considerable progress has been made in the discovery of DYRK1A inhibitors. Identification of pharmacophoric fragments provides valuable information for structure- and fragment-based design of potent and selective DYRK1A inhibitors. In this study, seven machine learning methods along with five molecular fingerprints were employed to develop qualitative classification models of DYRK1A inhibitors, which were evaluated by cross-validation, test set, and external validation set with four performance indicators of predictive classification accuracy (CA), the area under receiver operating characteristic (AUC), Matthews correlation coefficient (MCC), and balanced accuracy (BA). The PubChem fingerprint-support vector machine model (CA = 0.909, AUC = 0.933, MCC = 0.717, BA = 0.855) and PubChem fingerprint along with the artificial neural model (CA = 0.862, AUC = 0.911, MCC = 0.705, BA = 0.870) were considered as the optimal modes for training set and test set, respectively. A hybrid data balancing method SMOTETL, a combination of synthetic minority over-sampling technique (SMOTE) and Tomek link (TL) algorithms, was applied to explore the impact of balanced learning on the performance of models. Based on the frequency analysis and information gain, pharmacophoric fragments related to DYRK1A inhibition were also identified. All the results will provide theoretical supports and clues for the screening and design of novel DYRK1A inhibitors.

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Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

Cited by 27 publications

References 32 publications

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer

Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models

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