Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors

Anderson, K.; Chen, Yi; Chen, Zhi; Dominique, Romyr; Glenn, Kelli; He, Yang; Janson, Cheryl A.; Luk, Kin-chun; Lukacs, C.M.; Polonskaia, Ann; Qiao, Qi; Railkar, Aruna; Rossman, P.; Sun, Hongmao; Qiu, Xiang; Vilenchik, Maria; Wovkulich, Peter M.; Zhang, Xiaolei

doi:10.1016/j.bmcl.2013.10.055

Cited by 48 publications

(25 citation statements)

References 15 publications

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“…Given the potent and previously unrecognized splicing kinase inhibitory activity of these drugs against this kinase panel, we also decided to investigate the activity of other known splicing kinase inhibitory drugs and tool compounds that were not included in the initial TESLR screen. To this end we performed a dose-response screen with Mirk-IN-1 (a known DYRK1A inhibitor), (Anderson, Chen et al 2013) Sphinx31 (a selective SRPK1 inhibitor) (Batson, Toop et al 2017) dinaciclib (a FDA designated orphan drug and a potent CDK 1, 2, 5, and 9 inhibitor), (Paruch, Dwyer et al 2010) SRPIN340 (SRPK 1 and 2 inhibitor), (Karakama, Sakamoto et al 2010) SNS-032 (CDK 2,7 and 9 inhibitor), (Ma and Cress 2007) flavopiridol (Alvocidib, a FDA designated orphan drug and a potent pan-CDK inhibitor), (Senderowicz 1999) palbociclib (a non-selective CDK/multi-kinase inhibitor that is a FDA designated orphan drug), (Klaeger, Heinzlmeir et al 2017) and silmitasertib (a CK2 inhibitor in Phase II). (Kim, Choi et al 2014) Of these compounds we found that only Mirk-IN-1, palbociclib and silmitasertib were active (IC50s in the range of 10-300 µM) in the TESLR assay, while the other splicing kinase inhibitors showed IC50s >> 10 µM in inducing triple exon skipping (see SI; Figure S4).…”

Section: Focused Screening Of Selective Tool Compounds and Kinase Inhmentioning

confidence: 99%

An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

Shi

Bray²,

Smith³

et al. 2019

Preprint

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Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-030871) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further supports the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for chemotherapeutic discovery.

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Section: Focused Screening Of Selective Tool Compounds and Kinase Inhmentioning

confidence: 99%

An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

Shi

Bray²,

Smith³

et al. 2019

Preprint

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“…A pyrido[2,3-d]pyrimidine derivative was published as a Dyrk1B inhibitor; however it was three times more potent toward Dyrk1A and also inhibited microtubule affinity–regulating kinase (MARK)1 in a small counter screen [32]. This series was extended in a recent report, however, selectivity data or evidence for an inhibition of the target kinases in cells were not provided [61]. Some acridine analogs were found to potently inhibit Dyrk2, with only few kinases being affected outside the CMGC family [62].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of a Library of Lead-Like 2,4-Bisheterocyclic Substituted Thiophenes as Selective Dyrk/Clk Inhibitors

Schmitt

Kail²,

Mariano

et al. 2014

PLoS ONE

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The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform–mediated functions.

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“…1C). The free space was occupied by the other DYRK1A inhibitor pyrido [2,3-d]pyrimidine inhibitor, 20 and partly by leucettine L41 21 (Fig. S1), indicating that this space is available for structural modification of INDY.…”

Section: Structural Modification Of Indy Based On the Crystal Structumentioning

confidence: 95%

Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis

Masaki

Kii

Sumida

et al. 2015

Bioorganic & Medicinal Chemistry

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Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome.

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Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors

Cited by 48 publications

References 15 publications

An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

Design and Synthesis of a Library of Lead-Like 2,4-Bisheterocyclic Substituted Thiophenes as Selective Dyrk/Clk Inhibitors

Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis

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