Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies

Tong, Lexian; Song, Pinrao; Jiang, Kailong; Xu, Lei; Jin, Tingting; Wang, Peipei; Hu, Xiaobei; Sui, Fang; Gao, Anran; Zhou, Yubo; Liu, Tao; Li, Jia; Hu, Yongzhou

doi:10.1016/j.ejmech.2019.03.062

Cited by 20 publications

(11 citation statements)

References 34 publications

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“…As a continuation of our virtual screening work which identified new inhibitors targeting NIK, CHK1, Akt, etc. (18)(19)(20)(21)(22)(23)(24). In this study, we performed a traditional VS procedure to identify potential inhibitors of IRAK1.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel Interleukin-1 Receptor Associated Kinase-1 Inhibitors

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel Interleukin-1 Receptor Associated Kinase-1 Inhibitors

et al. 2020

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“…Compound 1 is a potent and selective CHK1 inhibitor, which could suppress the proliferation of hematologic malignancies . However, it was found to have poor oral bioavailability and was, thus, administered intravenously.…”

Section: Resultsmentioning

confidence: 99%

“…Considering that the AUC of compound 2b was slightly better than that of 2a , the trifluoromethyl motif was selected for further research. In our previous study, we found that the 3-position of pyridine could be oriented to the ribose region of CHK1 to form a hydrogen bond with CHK1 protein, which is important for CHK1 inhibitory activity. Various basic substitutions (R) and the linker (X) were investigated to improve CHK1 inhibition (Table ).…”

Section: Resultsmentioning

confidence: 99%

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Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile

Jin

Wang

et al. 2021

J. Med. Chem.

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Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anticancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

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“…LY2606368, a CHK1/CHK2 dual inhibitor, preferentially inhibits CHK1 in vitro , which results in increased CDC25A activity and leads to the activation of CDK2 . Several other CHK1 inhibitors, including CCT244747, SAR-020106, MCL1020, and MU380, are being developed and tested preclinically. Although many CHK1 inhibitors have shown promising results in vitro , they have not yielded impressive outcomes in clinical trials .…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomics Analysis Reveals a Potential Role of CHK1 in Regulation of Innate Immunity through IRF3

et al. 2020

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Inhibitors of checkpoint kinase 1 (CHK1), a central component of DNA damage and cell cycle checkpoint response, represent a promising new cancer therapy, but the global cellular functions they regulate through phosphorylation are poorly understood. To elucidate the CHK1-regulated phosphorylation network, we performed a global quantitative phosphoproteomics analysis, which revealed 142 phosphosites whose phosphorylation levels were significantly different following treatment with the CHK1 inhibitor SCH 900776. Bioinformatics analysis identified phosphoproteins that function in ATR–CHK1 signaling, DNA replication, and DNA repair. Furthermore, IRF3 phosphorylation at S173 and S175 was significantly reduced following treatment with SCH 900776. Our findings indicate that the CHK1-dependent regulation of IRF3 phosphorylation at S173 and S175 may play a role in the induction of innate immune response after replication stress or DNA damage, which suggests a potential function of CHK1 in the innate immune response. Data are available via ProteomeXchange with identifier PXD015125.

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Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies

Cited by 20 publications

References 34 publications

Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel Interleukin-1 Receptor Associated Kinase-1 Inhibitors

Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel Interleukin-1 Receptor Associated Kinase-1 Inhibitors

Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile

Phosphoproteomics Analysis Reveals a Potential Role of CHK1 in Regulation of Innate Immunity through IRF3

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