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<p>We report the design and synthesis of PROTACs based on (3 R,4 R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)piperidin-3-ol, using diverse linkers and pomalidomide as a CRBN ligand. Molecular modeling experiments were conducted to arrive at the optimal exit vectors on both the warhead and pomalidomide to enable efficient linker attachment. Most of the PROTACs exhibited good binding affinity (IC<sub>50</sub> between 0.04 µM to 1.50 µM) with CDK4/6 and the binary complex formation data correlated with the ternary complex formation. Selected PROTACs (compounds <b>4</b>, <b>7</b>, and <b>13</b>) were tested in Jurkat cells at varying concentrations to assess CDK4/6 protein degradation. Compound <b>7</b> showed a DC<sub>50</sub> of 2.0 and 4.0 nM against CDK4 and CDK6 respectively, whereas compound <b>13</b> showed a DC<sub>50</sub> of 6.0 nM against both CDK4 and CDK6. These results highlight PROTACs <b>7</b> and <b>13</b> as promising leads for further therapeutic development.</p><p></p>

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Design, synthesis and profiling of proteolysis-targeting chimeras (PROTACs) as CDK4/6 degraders

  • 期刊论文

  • 发表日期：

    2025年6月23日

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  • Rajeev Goswami,
  • Nimesh Bhaskaran,
  • Anil Deshpande,
  • Neha KS,
  • Anand Kumar Raichurkar,
  • Anirudh Manoj,
  • Anil Srivastava,
  • Amit Singh,
  • Srividya Swaminathan,
  • Jeyaraj Duraiswamy Athisayamani,
  • Saravanakumar Dhakshinamoorthy

摘要

We report the design and synthesis of PROTACs based on (3 R,4 R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)piperidin-3-ol, using diverse linkers and pomalidomide as a CRBN ligand. Molecular modeling experiments were conducted to arrive at the optimal exit vectors on both the warhead and pomalidomide to enable efficient linker attachment. Most of the PROTACs exhibited good binding affinity (IC50 between 0.04 µM to 1.50 µM) with CDK4/6 and the binary complex formation data correlated with the ternary complex formation. Selected PROTACs (compounds 4, 7, and 13) were tested in Jurkat cells at varying concentrations to assess CDK4/6 protein degradation. Compound 7 showed a DC50 of 2.0 and 4.0 nM against CDK4 and CDK6 respectively, whereas compound 13 showed a DC50 of 6.0 nM against both CDK4 and CDK6. These results highlight PROTACs 7 and 13 as promising leads for further therapeutic development.