Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells.

The RAF/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC50 values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC50= 2.8 μM) compared to A549 cells (IC50 = 27.3 μM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human cancer cells.

[1]  Guangrong Zheng,et al.  Overcoming Cancer Drug Resistance Utilizing PROTAC Technology , 2022, Frontiers in Cell and Developmental Biology.

[2]  Chao Wang,et al.  The state of the art of PROTAC technologies for drug discovery. , 2022, European journal of medicinal chemistry.

[3]  D. Langley,et al.  PROTAC targeted protein degraders: the past is prologue , 2022, Nature Reviews Drug Discovery.

[4]  Kanyi Pu,et al.  Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy , 2021, Nature Communications.

[5]  Yan Niu,et al.  Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer. , 2021, European journal of medicinal chemistry.

[6]  Xian Chen,et al.  Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders. , 2020, Journal of medicinal chemistry.

[7]  Guoshun Luo,et al.  Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. , 2020, European journal of medicinal chemistry.

[8]  C. Crews,et al.  Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs , 2020, ACS central science.

[9]  M. Perry,et al.  Design, synthesis and biological evaluation of MEK PROTACs. , 2019, Journal of medicinal chemistry.

[10]  Xian Chen,et al.  Discovery of a First-in-class Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Degrader. , 2019, Journal of medicinal chemistry.

[11]  A. Ferrando,et al.  A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity , 2019, Nature Medicine.

[12]  M. Koegl,et al.  BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design , 2019 .

[13]  M. Shirley.  Encorafenib and Binimetinib: First Global Approvals , 2018, Drugs.

[14]  J. Byrd,et al.  Targeting the C481S Ibrutinib-Resistance Mutation in Bruton's Tyrosine Kinase Using PROTAC-Mediated Degradation. , 2018, Biochemistry.

[15]  Karen E Crowell,et al.  Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism , 2017, Cardiovascular Toxicology.

[16]  J. Ovádi,et al.  Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). , 2017, Journal of medicinal chemistry.

[17]  Eunhwa Ko,et al.  Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. , 2016, Angewandte Chemie.

[18]  G. Linette,et al.  Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. , 2014, JAMA.

[19]  M. Sakaitani,et al.  Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning. , 2014, ACS medicinal chemistry letters.

[20]  Wei Xu,et al.  Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. , 2013, Cell reports.

[21]  Noriyuki Furuichi,et al.  Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties. , 2013, ACS medicinal chemistry letters.

[22]  Yan Niu,et al.  Substituted 3-Benzylcoumarins as Allosteric MEK1 Inhibitors: Design, Synthesis and Biological Evaluation as Antiviral Agents , 2013, Molecules.

[23]  S J Cook,et al.  Mechanisms of acquired resistance to ERK1/2 pathway inhibitors , 2013, Oncogene.

[24]  W. Sellers,et al.  MEK1 mutations confer resistance to MEK and B-RAF inhibition , 2009, Proceedings of the National Academy of Sciences.