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Generation of highly potent DYRK1A-dependent inducers of human ?-Cell replication via Multi-Dimensional compound optimization.

ABSTRACT: Small molecule stimulation of ?-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance ?-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human ?-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human ?-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human ?-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

SUBMITTER: Allegretti PA

PROVIDER: S-EPMC6941846 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization.

Allegretti Paul A PA Horton Timothy M TM Abdolazimi Yassan Y Moeller Hannah P HP Yeh Benjamin B Caffet Matthew M Michel Guillermina G Smith Mark M Annes Justin P JP

Bioorganic & medicinal chemistry 20191111 1

Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cel ...[more]

PMID: 31757680

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Project description:BackgroundDNA methyltransferases (DNMTs) are epigenetic enzymes involved in embryonic development, cell differentiation, epithelial to mesenchymal transition, and control of gene expression, whose overexpression or enhanced catalytic activity has been widely reported in cancer initiation and progression. To date, two DNMT inhibitors (DNMTi), 5-azacytidine (5-AZA) and 5-aza-2'-deoxycytidine (DAC), are approved for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Nevertheless, they are chemically instable and quite toxic for healthy cells; thus, the discovery of novel DNMTi is urgent.ResultsHere, we report the identification of a new quinoline-based molecule, MC3353, as a non-nucleoside inhibitor and downregulator of DNMT. This compound was able, in promoter demethylating assays, to induce enhanced green fluorescence protein (EGFP) gene expression in HCT116 cells and transcription in a cytomegalovirus (CMV) promoter-driven luciferase reporter system in KG-1 cells. Moreover, MC3353 displayed a strong antiproliferative activity when tested on HCT116 colon cancer cells after 48?h of treatment at 0.5??M. At higher doses, this compound provided a cytotoxic effect in double DNMT knockout HCT116 cells. MC3353 was also screened on a different panel of cancer cells (KG-1 and U-937 acute myeloid leukemia, RAJI Burkitt's lymphoma, PC-3 prostate cancer, and MDA-MB-231 breast cancer), where it arrested cell proliferation and reduced viability after 48?h of treatment with IC50 values ranging from 0.3 to 0.9??M. Compared to healthy cell models, MC3353 induced apoptosis (e.g., U-937 and KG-1 cells) or necrosis (e.g., RAJI cells) at lower concentrations. Importantly, together with the main DNMT3A enzyme inhibition, MC3353 was also able to downregulate the DNMT3A protein level in selected HCT116 and PC-3 cell lines. Additionally, this compound provided impairment of the epithelial-to-mesenchymal transition (EMT) by inducing E-cadherin while reducing matrix metalloproteinase (MMP2) mRNA and protein levels in PC-3 and HCT116 cells. Last, tested on a panel of primary osteosarcoma cell lines, MC3353 markedly inhibited cell growth with low single-digit micromolar IC50 ranging from 1.1 to 2.4??M. Interestingly, in Saos-2 osteosarcoma cells, MC3353 induced both expression of genes and mineralized the matrix as evidence of osteosarcoma to osteoblast differentiation.ConclusionsThe present work describes MC3353 as a novel DNMTi displaying a stronger in cell demethylating ability than both 5-AZA and DAC, providing re-activation of the silenced ubiquitin C-terminal hydrolase L1 (UCHL1) gene. MC3353 displayed dose- and time-dependent antiproliferative activity in several cancer cell types, inducing cell death and affecting EMT through E-cadherin and MMP2 modulation. In addition, this compound proved efficacy even in primary osteosarcoma cell models, through the modulation of genes involved in osteoblast differentiation.

Project description:Genomic selection is a worthy breeding method to improve genetic gain in recurrent selection breeding schemes. The integration of multi-generation and multi-location information could significantly improve genomic prediction models in the context of shuttle breeding. The Cirad-CIAT upland rice breeding program applies recurrent genomic selection and seeks to optimize the scheme to increase genetic gain while reducing phenotyping efforts. We used a synthetic population (PCT27) of which S0 plants were all genotyped and advanced by selfing and bulk seed harvest to the S0:2, S0:3, and S0:4 generations. The PCT27 was then divided into two sets. The S0:2 and S0:3 progenies for PCT27A and the S0:4 progenies for PCT27B were phenotyped in two locations: Santa Rosa the target selection location, within the upland rice growing area, and Palmira, the surrogate location, far from the upland rice growing area but easier for experimentation. While the calibration used either one of the two sets phenotyped in one or two locations, the validation population was only the PCT27B phenotyped in Santa Rosa. Five scenarios of genomic prediction and 24 models were performed and compared. Training the prediction model with the PCT27B phenotyped in Santa Rosa resulted in predictive abilities ranging from 0.19 for grain zinc concentration to 0.30 for grain yield. Expanding the training set with the inclusion of the PCT27A resulted in greater predictive abilities for all traits but grain yield, with increases from 5% for plant height to 61% for grain zinc concentration. Models with the PCT27B phenotyped in two locations resulted in higher prediction accuracy when the models assumed no genotype-by-environment (G × E) interaction for flowering (0.38) and grain zinc concentration (0.27). For plant height, the model assuming a single G × E variance provided higher accuracy (0.28). The gain in predictive ability for grain yield was the greatest (0.25) when environment-specific variance deviation effect for G × E was considered. While the best scenario was specific to each trait, the results indicated that the gain in predictive ability provided by the multi-location and multi-generation calibration was low. Yet, this approach could lead to increased selection intensity, acceleration of the breeding cycle, and a sizable economic advantage for the program.

Dataset Information

Generation of highly potent DYRK1A-dependent inducers of human ?-Cell replication via Multi-Dimensional compound optimization.

Publications

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization.

Similar Datasets

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