Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation
Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CD...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/2951 |
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| author | Biruk Sintayehu Fanta Jimma Lenjisa Theodosia Teo Lianmeng Kou Laychiluh Mekonnen Yuchao Yang Sunita K. C. Basnet Ramin Hassankhani Matthew J. Sykes Mingfeng Yu Shudong Wang |
| author_facet | Biruk Sintayehu Fanta Jimma Lenjisa Theodosia Teo Lianmeng Kou Laychiluh Mekonnen Yuchao Yang Sunita K. C. Basnet Ramin Hassankhani Matthew J. Sykes Mingfeng Yu Shudong Wang |
| author_sort | Biruk Sintayehu Fanta |
| collection | DOAJ |
| description | Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound <b>1</b> was bioisosterically replaced with pyrazole derivatives, affording a novel series of <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, <b>15</b> was the most potent CDK2 inhibitor (<i>K</i><sub>i</sub> = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI<sub>50</sub> = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that <b>15</b> reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer. |
| first_indexed | 2024-03-11T05:30:13Z |
| format | Article |
| id | doaj.art-e7f7255ec5e440348ed681432266d49d |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:30:13Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e7f7255ec5e440348ed681432266d49d2023-11-17T17:11:21ZengMDPI AGMolecules1420-30492023-03-01287295110.3390/molecules28072951Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and EvaluationBiruk Sintayehu Fanta0Jimma Lenjisa1Theodosia Teo2Lianmeng Kou3Laychiluh Mekonnen4Yuchao Yang5Sunita K. C. Basnet6Ramin Hassankhani7Matthew J. Sykes8Mingfeng Yu9Shudong Wang10Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaCyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound <b>1</b> was bioisosterically replaced with pyrazole derivatives, affording a novel series of <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, <b>15</b> was the most potent CDK2 inhibitor (<i>K</i><sub>i</sub> = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI<sub>50</sub> = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that <b>15</b> reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.https://www.mdpi.com/1420-3049/28/7/2951CDK2CDK2 inhibitorpyrazole<i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amineantiproliferative activitybioisosteric replacement |
| spellingShingle | Biruk Sintayehu Fanta Jimma Lenjisa Theodosia Teo Lianmeng Kou Laychiluh Mekonnen Yuchao Yang Sunita K. C. Basnet Ramin Hassankhani Matthew J. Sykes Mingfeng Yu Shudong Wang Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation Molecules CDK2 CDK2 inhibitor pyrazole <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine antiproliferative activity bioisosteric replacement |
| title | Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation |
| title_full | Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation |
| title_fullStr | Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation |
| title_full_unstemmed | Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation |
| title_short | Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation |
| title_sort | discovery of i n i 4 di 1 i h i pyrazol 4 yl pyrimidin 2 amine derived cdk2 inhibitors as potential anticancer agents design synthesis and evaluation |
| topic | CDK2 CDK2 inhibitor pyrazole <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine antiproliferative activity bioisosteric replacement |
| url | https://www.mdpi.com/1420-3049/28/7/2951 |
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