Development of CDK4/6 Inhibitors: Comparison
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by MARIALUIGIA FANTACUZZI.

CDKs, a family of serine/threonine kinases, regulate cell cycle progression into the four distinct phases G1, S (DNA synthesis), G2 and M, and are crucially involved in the regulation of cell division and proliferation.

  • cyclin-dependent kinase
  • cancer
  • resistance
  • small molecule inhibitors
  • PROTACs
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References

  1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.
  2. Dai, X.; Li, T.; Bai, Z.; Yang, Y.; Liu, X.; Zhan, J.; Shi, B. Breast cancer intrinsic subtype classification, clinical use and future trends. Am. J. Cancer. Res. 2015, 5, 2929–2943.
  3. Hu, Z.; Fan, C.; Oh, D.S.; Marron, J.S.; He, X.; Qaqish, B.F.; Livasy, C.; Carey, L.A.; Reynolds, E.; Dressler, L.; et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genom. 2006, 7, 96.
  4. Lehmann, B.D.; Bauer, J.A.; Chen, X.; Sanders, M.E.; Chakravarthy, A.B.; Shyr, Y.; Pietenpol, J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Investig. 2011, 121, 2750–2767.
  5. Tao, M.; Song, T.; Du, W.; Han, S.; Zuo, C.; Li, Y.; Wang, Y.; Yang, Z. Classifying breast cancer subtypes using multiple kernel learning based on bmics data. Genes 2019, 10, 200.
  6. Aggelis, V.; Johnston, S.R.D. Advances in endocrine-based therapies for estrogen receptor-positive metastatic breast cancer. Drugs 2019, 79, 1849–1866.
  7. Jordan, V.C.; O’Malley, B.W. Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J. Clin. Oncol. 2007, 25, 5815–5824.
  8. Gombos, A. Selective oestrogen receptor degraders in breast cancer: A review and perspectives. Curr. Opin. Oncol. 2019, 31, 424–429.
  9. Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 2015, 386, 1341–1352.
  10. Portman, N.; Alexandrou, S.; Carson, E.; Wang, S.; Lim, E.; Caldon, E. Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. Endocr. Relat. Cancer. 2019, 26, R15–R30.
  11. Dutta, U.; Pant, K. Aromatase inhibitors: Past, present and future in breast cancer therapy. Med. Oncol. 2008, 25, 113–124.
  12. Kharb, R.; Haider, K.; Neha, K.; Yar, M.S. Aromatase inhibitors: Role in postmenopausal breast cancer. Arch. Pharm. 2020, 353, e2000081.
  13. Ghosh, D.; Lo, J.; Morton, D.; Valette, D.; Xi, J.; Griswold, J.; Hubbell, S.; Egbuta, C.; Jiang, W.; An, J.; et al. Novel aromatase inhibitors by structure-guided design. J. Med. Chem. 2012, 55, 8464–8476.
  14. Fantacuzzi, M.; De Filippis, B.; Gallorini, M.; Ammazzalorso, A.; Giampietro, L.; Maccallini, C.; Aturki, Z.; Donati, E.; Ibrahim, R.S.; Shawky, E.; et al. Synthesis, biological evaluation, and docking study of indole arylsulfonamides as aromatase inhibitors. Eur. J. Med. Chem. 2020, 185, 111815.
  15. Di Matteo, M.; Ammazzalorso, A.; Andreoli, F.; Caffa, I.; De Filippis, B.; Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Nencioni, A.; Parenti, M.D.; et al. Synthesis and biological characterization of 3-(imidazole-1-ylmethyl) piperidine sulfonamides as aromatase inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 3192–3194.
  16. Ammazzalorso, A.; Gallorini, M.; Fantacuzzi, M.; Gambacorta, N.; De Filippis, B.; Giampietro, L.; Maccallini, C.; Nicolotti, O.; Cataldi, A.; Amoroso, R. Design, synthesis and biological evaluation of imidazole and triazole-based carbamates as novel aromatase inhibitors. Eur. J. Med. Chem. 2021, 211, 113115.
  17. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70.
  18. Hanker, A.B.; Sudhan, D.R.; Arteaga, C.L. Overcoming endocrine resistance in breast cancer. Cancer Cell 2020, 37, 496–513.
  19. Kalra, S.; Joshi, G.; Munshi, A.; Kumar, R. Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. Eur. J. Med. Chem. 2017, 142, 424–458.
  20. Zhang, J.; Yang, P.L.; Gray, N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 2009, 9, 28–39.
  21. Scheiblecker, L.; Kollmann, K.; Sexl, V. CDK4/6 and MAPK-crosstalk as opportunity for cancer treatment. Pharmaceuticals 2020, 13, 418.
  22. Malumbres, M. Cyclin-dependent kinases. Genome Biol. 2014, 15, 122.
  23. Malumbres, M.; Harlow, E.; Hunt, T.; Hunter, T.; Lahti, J.M.; Manning, G.; Morgan, D.O.; Tsai, L.H.; Wolgemuth, D.J. Cyclin-dependent kinases: A family portrait. Nat. Cell Biol. 2009, 11, 1275–1276.
  24. Kollmann, K.; Heller, G.; Schneckenleithner, C.; Warsch, W.; Scheicher, R.; Ott, R.G.; Schafer, M.; Fajmann, S.; Schlederer, M.; Schiefer, A.I.; et al. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 2013, 24, 167–181.
  25. Roovers, K.; Assoian, R.K. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. BioEssays 2000, 22, 818–826.
  26. Xiong, Y.; Li, T.; Assani, G.; Ling, H.; Zhou, Q.; Zeng, Y.; Zhou, F.; Zhou, Y. Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo. Biomed. Pharmacother. 2019, 112, 108602–108613.
  27. Roskoski, R., Jr. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol. Res. 2016, 107, 249–275.
  28. Lynce, F.; Shajahan-Haq, A.N.; Swain, S.M. CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. Pharmacol. Ther. 2018, 191, 65–73.
  29. Peyressatre, M.; Prével, C.; Pellerano, M.; Morris, M.C. Targeting cyclin-dependent kinases in human cancers: From small molecules to peptide inhibitors. Cancers 2015, 7, 179–237.
  30. Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 2015, 14, 130–146.
  31. Pernas, S.; Tolaney, S.M.; Winer, E.P.; Goel, S. CDK4/6 inhibition in breast cancer: Current practice and future directions. Ther. Adv. Med. Oncol. 2018, 10, 1758835918786451.
  32. Goel, S.; DeCristo, M.J.; McAllister, S.S.; Zhao, J.J. CDK4/6 inhibition in cancer: Beyond cell cycle arrest. Trends Cell Biol. 2018, 28, 911–925.
  33. Dos Santos Paparidis, N.F.; Canduri, F. The emerging picture of CDK11: Genetic, functional and medicinal aspects. Curr. Med. Chem. 2018, 25, 880–888.
  34. Shazzad Hossain Prince, G.M.; Yang, T.-Y.; Lin, H.; Chen, M.-C. Mechanistic insight of cyclin-dependent kinase 5 in modulating lung cancer growth. Chin. J. Physiol. 2019, 62, 231–240.
  35. Pozo, K.; Bibb, J.A. The emerging role of Cdk5 in cancer. Trends Cancer 2016, 2, 606–618.
  36. Xi, M.; Chen, T.; Wu, C.; Gao, Z.; Wu, Y.; Luo, X.; Du, K.; Yu, L.; Cai, T.; Shen, R.; et al. CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors. Eur. J. Med. Chem. 2019, 164, 77–91.
  37. Eyvazis, S.; Hejazi, M.S.; Kahora, H.; Abasi, M.; Zamiri, R.E.; Tarhriz, V. CDK9 as an appealing target for therapeutic interventions. Curr. Drug Targets 2019, 20, 453–464.
  38. Bose, P.; Simmons, G.L.; Grant, S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin. Investig. Drugs 2013, 22, 723–738.
  39. Blum, K.A.; Ruppert, A.S.; Woyach, J.A.; Jones, J.A.; Andritsos, L.; Flynn, J.M.; Rovin, B.; Villalona-Calero, M.; Ji, J.; Phelps, M.; et al. Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. Leukemia 2011, 25, 1444–1451.
  40. Le Tourneau, C.; Faivre, S.; Laurence, V.; Delbaldo, C.; Vera, K.; Girre, V.; Chiao, J.; Armour, S.; Frame, S.; Green, S.R.; et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur. J. Cancer 2010, 46, 3243–3250.
  41. Payton, M.; Chung, G.; Yakowec, P.; Wong, A.; Powers, D.; Xiong, L.; Zhang, N.; Leal, J.; Bush, T.L.; Santora, V.; et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res. 2006, 66, 4299–4308.
  42. Parry, D.; Guzi, T.; Shanahan, F.; Davis, N.; Prabhavalkar, D.; Wiswell, D.; Seghezzi, W.; Paruch, K.; Dwyer, M.P.; Doll, R.; et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 2010, 9, 2344–2353.
  43. Teng, Y.; Lu, K.; Zhang, Q.; Zhao, L.; Huang, Y.; Ingarra, A.M.; Galons, H.; Li, T.; Cui, S.; Yu, P.; et al. Recent advances in the development of cyclin-dependent kinase 7 inhibitors. Eur. J. Med. Chem. 2019, 183, 1116412.
  44. Czudor, Z.; Balogh, M.; Bánhegyi, P.; Boros, S.; Breza, N.; Dobos, J.; Fábián, M.; Horváth, Z.; Illyés, E.; Markó, P.; et al. Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma. Bioorg. Med. Chem. Lett. 2018, 28, 769–773.
  45. Dukelow, T.; Kishan, D.; Khasraw, M.; Murphy, C.G. CDK4/6 inhibitors in breast cancer. Anticancer Drugs 2015, 26, 797–806.
  46. Poratti, M.; Marzaro, G. Third-generation CDK inhibitors: A review on the synthesis and binding modes of palbociclib, ribociclib and abemaciclib. Eur. J. Med. Chem. 2019, 172, 143–153.
  47. Beaver, J.A.; Amiri-Kordestani, L.; Charlab, R.; Chen, W.; Palmby, T.; Tilley, A.; Zirkelbach, J.F.; Yu, J.; Liu, Q.; Zhao, L.; et al. FDA approval: Palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin. Cancer Res. 2015, 21, 4760–4766.
  48. Syed, Y.Y. Ribociclib: First global approval. Drugs 2017, 77, 799–807.
  49. Patnaik, A.; Rosen, L.S.; Tolaney, S.M.; Tolcher, A.W.; Goldman, J.W.; Gandhi, L.; Papadopoulos, K.P.; Beeram, M.; Rasco, D.W.; Hilton, J.F.; et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016, 6, 740–753.
  50. Tan, A.R.; Wright, G.S.; Thummala, A.R.; Danso, M.A.; Popovic, L.; Pluard, T.J.; Han, H.S.; Vojnović, Ž.; Vasev, N.; Ma, L.; et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: A multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019, 20, 1587–1601.
  51. Hart, L.L.; Ferrarotto, R.; Andric, Z.G.; Beck, J.T.; Subramanian, J.T.; Radosavljevic, D.Z.; Zaric, B.; Hanna, W.T.; Aljumaily, R.; Owonikoko, T.K.; et al. Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: Results from a randomized, double-blind, placebo-controlled phase II study. Adv. Ther. 2021, 38, 350–365.
  52. Bisi, J.E.; Sorrentino, J.A.; Roberts, P.J.; Tavares, F.X.; Strum, J.C. Preclinical characterization of G1T28: A novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol. Cancer Ther. 2016, 15, 783–793.
  53. He, S.; Roberts, P.J.; Sorrentino, J.A.; Bisi, J.E.; Storrie-White, H.; Tiessen, R.G.; Makhuli, K.M.; Wargin, W.A.; Tadema, H.; van Hoogdalem, E.J.; et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci. Transl. Med. 2017, 9, eaal3986.
  54. Bisi, J.E.; Sorrentino, J.A.; Jordan, J.L.; Darr, D.D.; Roberts, P.J.; Tavares, F.X.; Strum, J.C. Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget 2017, 8, 42343–42358.
  55. Stice, J.P.; Wardell, S.E.; Norris, J.D.; Yllanes, A.P.; Alley, H.M.; Haney, V.O.; White, H.S.; Safi, R.; Winter, P.S.; Cocce, K.J.; et al. CDK4/6 therapeutic intervention and viable alternative to taxanes in CRPC. Mol. Cancer Res. 2017, 15, 660–669.
  56. Long, F.; He, Y.; Fu, H.; Li, Y.; Bao, X.; Wang, Q.; Wang, Y.; Xie, C.; Lou, L. Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models. Cancer Sci. 2019, 110, 1420–1430.
  57. Wang, J.; Li, Q.; Yuan, J.; Wang, J.; Chen, Z.; Liu, Z.; Li, Z.; Lai, Y.; Gao, J.; Shen, L. CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest. J. Transl. Med. 2017, 15, 127.
  58. Wang, Y.; Wang, J.; Ding, L. Benzimidazole Derivatives, Preparation Methods and Uses Thereof. PCT. International Patent WO2016145622A1, 22 September 2016.
  59. Gelbert, L.M.; Cai, S.; Lin, X.; Sanchez-Martinez, C.; del Prado, M.; Lallena, M.J.; Torres, R.; Ajamie, R.T.; Wishart, G.N.; Flack, R.S.; et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Investig. New Drugs 2014, 32, 825–837.
  60. Tate, S.C.; Cai, S.; Ajamie, R.T.; Burke, T.; Beckmann, R.P.; Chan, E.M.; De Dios, A.; Wishart, G.N.; Gelbert, L.M.; Cronier, D.M. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin. Cancer Res. 2014, 20, 3763.
  61. Rader, J.; Russell, M.R.; Hart, L.S.; Nakazawa, M.S.; Belcastro, L.T.; Martinez, D.; Li, Y.; Carpenter, E.L.; Attiyeh, E.F.; Diskin, S.J.; et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 2013, 19, 6173.
  62. Chen, P.; Lee, N.V.; Hu, W.; Xu, M.; Ferre, R.A.; Lam, H.; Bergqvist, S.; Solowiej, J.; Diehl, W.; He, Y.A.; et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol. Cancer Ther. 2016, 15, 2273.
  63. Tsai, C.J.; Nussinov, R. The molecular basis of targeting protein kinases in cancer therapeutics. Semin. Cancer Biol. 2013, 23, 235–242.
  64. Hojjat-Farsangi, M. Small-molecule inhibitors of the receptor tyrosine kinases: Promising tools for targeted cancer therapies. Int. J. Mol. Sci. 2014, 15, 13768–13801.
  65. Zhou, M.; Wang, R. Small-molecule regulators of autophagy and their potential therapeutic applications. ChemMedChem 2013, 8, 694–707.
  66. Roskoski, R., Jr. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol. Res. 2015, 100, 1–23.
  67. Roskoski, R., Jr. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol. Res. 2019, 144, 19–50.
  68. Meisel, J.E.; Chang, M. Selective small-molecule inhibitors as chemical tools to define the roles of matrix metalloproteinases in disease. BBA Mol. Cell Res. 2017, 1864, 2001–2014.
  69. Tadesse, S.; Yu, M.; Mekonnen, L.B.; Lam, F.; Islam, S.; Tomusange, K.; Rahaman, M.H.; Noll, B.; Basnet, S.K.C.; Teo, T.; et al. Highly potent, selective, and orally bioavailable 4-thiazol N-(pyridin-2-yl)pyrimidin-2-amine cyclin-dependent kinases 4 and 6 inhibitors as anticancer drug candidates: Design, synthesis, and evaluation. J. Med. Chem. 2017, 60, 1892–1915.
  70. Shao, H.; Shi, S.; Huang, S.; Hole, A.J.; Abbas, A.Y.; Baumli, S.; Liu, X.; Lam, F.; Foley, D.W.; Fischer, P.M.; et al. Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: Synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J. Med. Chem. 2013, 56, 640–659.
  71. Tadesse, S.; Zhu, G.; Mekonnen, L.B.; Lenjisa, J.L.; Yu, M.; Brown, M.P.; Wang, S. A novel series of N-(pyridin-2-yl)-4-(thiazol5-yl)pyrimidin-2-amines as highly potent CDK4/6 inhibitors. Future Med. Chem. 2017, 9, 1495–1506.
  72. Tadesse, S.; Bantie, L.; Tomusange, K.; Yu, M.; Islam, S.; Bykovska, N.; Noll, B.; Zhu, G.; Li, P.; Lam, F.; et al. Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents. Br. J. Pharmacol. 2018, 175, 2399–2413.
  73. Zha, C.; Deng, W.; Fu, Y.; Tang, S.; Lan, X.; Ye, Y.; Su, Y.; Jiang, L.; Chen, Y.; Huang, Y.; et al. Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy. Eur. J. Med. Chem. 2018, 148, 140–153.
  74. Fu, Y.; Tang, S.; Su, Y.; Lan, X.; Ye, Y.; Zha, C.; Li, L.; Cao, J.; Chen, Y.; Jiang, L.; et al. Discovery of a class of diheteroaromatic amines as orally bioavailable CDK1/4/6 inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 5332–5336.
  75. Wang, Y.; Liu, W.-J.; Yin, L.; Li, H.; Chen, Z.-H.; Zhu, D.-X.; Song, X.-Q.; Cheng, Z.-Z.; Song, P.; Wang, Z.; et al. Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a] imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl) pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships. Bioorg. Med. Chem. Lett. 2018, 28, 974–978.
  76. Shi, C.; Wang, Q.; Liao, X.; Ge, H.; Huo, G.; Zhang, L.; Chen, N.; Zhai, X.; Hong, Y.; Wang, L.; et al. Discovery of 6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine as a highly potent cyclin-dependent kinase 4/6 inhibitor for treatment of cancer. Eur. J. Med. Chem. 2019, 178, 352–364.
  77. Abbas, S.E.-S.; George, R.F.; Samir, E.M.; Aref, M.M.A.; Abdel-Aziz, H.A. Synthesis and anticancer activity of some pyrido[2,3-d]pyrimidine derivatives as apoptosis inducers and cyclin-dependent kinase inhibitors. Future Med. Chem. 2019, 11, 2395–2414.
  78. Shi, C.; Wang, Q.; Liao, X.; Ge, H.; Huo, G.; Zhang, L.; Chen, N.; Zhai, X.; Hong, Y.; Wang, L.; et al. Discovery of a novel series of imidazo[10,2′:1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors. Eur. J. Med. Chem. 2020, 193, 112239.
  79. Zhao, H.; Hu, X.; Cao, K.; Zhang, Y.; Zhao, K.; Tang, C.; Feng, B. Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors. Eur. J. Med. Chem. 2018, 157, 935–945.
  80. Garg, M.; Chauhan, M.; Singh, P.K.; Alex, J.M.; Kumar, R. Pyrazoloquinazolines: Synthetic strategies and bioactivities. Eur. J. Med. Chem. 2015, 97, 444–461.
  81. Toure, M.; Crews, C.M. Small-molecule PROTACS: New approaches to protein degradation. Angew. Chem. Int. Ed. Engl. 2016, 55, 1966–1973.
  82. Lai, A.C.; Crews, C.M. Induced protein degradation: An emerging drug discovery paradigm. Nat. Rev. Drug Discov. 2017, 16, 101–114.
  83. Marak, B.N.; Dowarah, J.; Khiangte, L.; Singh, V.P. A comprehensive insight on the recent development of cyclic dependent kinase inhibitors as anticancer agents. Eur. J. Med. Chem. 2020, 203, 112571.
  84. Crews, C.M. Targeting the undruggable proteome: The small molecules of my dreams. Chem. Biol. 2010, 17, 551–555.
  85. Li, X.; Song, Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J. Hematol. Oncol. 2020, 13, 50.
  86. Gadd, M.S.; Testa, A.; Lucas, X.; Chan, K.-H.; Chen, W.; Lamont, D.J.; Zengerle, M.; Ciulli, A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 2017, 13, 514–521.
  87. Gao, H.; Sun, X.; Rao, Y. PROTAC technology: Opportunities and challenges. ACS Med. Chem. Lett. 2020, 11, 237–240.
  88. Robb, C.M.; Contreras, J.I.; Kour, S.; Taylor, M.A.; Abid, M.; Sonawane, Y.A.; Zahid, M.; Murry, D.J.; Natarajan, A.; Rana, S. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem. Commun. 2017, 53, 7577–7580.
  89. Hatcher, J.M.; Wang, E.S.; Johannessen, L.; Kwiatkowski, N.; Sim, T.; Gray, N.S. Development of highly potent and selective steroidal inhibitors and degraders of CDK8. ACS Med. Chem. Lett. 2018, 9, 540–545.
  90. Zhao, B.; Burgess, K. PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer. Chem. Commun. 2019, 55, 2704–2707.
  91. Rana, S.; Bendjennat, M.; Kour, S.; King, H.M.; Kizhake, S.; Zahid, M.; Natarajan, A. Selective degradation of CDK6 by a palbociclib based PROTAC. Bioorg. Med. Chem. Lett. 2019, 29, 1375–1379.
  92. Su, S.; Yang, Z.; Gao, H.; Yang, H.; Zhu, S.; An, Z.; Wang, J.; Li, Q.; Chandarlapaty, S.; Deng, H.; et al. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders. J. Med. Chem. 2019, 62, 7575–7582.
  93. Jiang, B.; Wang, E.S.; Donovan, K.A.; Liang, Y.; Fischer, E.S.; Zhang, T.; Gray, N.S. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew. Chem. Int. Ed. 2019, 58, 6321–6326.
  94. Lu, G.; Middleton, R.E.; Sun, H.; Naniong, M.; Ott, C.J.; Mitsiades, C.S.; Wong, K.K.; Bradner, J.E.; Kaelin, W.G., Jr. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014, 343, 305–309.
  95. Kronke, J.; Udeshi, N.D.; Narla, A.; Grauman, P.; Hurst, S.N.; McConkey, M.; Svinkina, T.; Heckl, D.; Comer, E.; Li, X.; et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014, 343, 301–305.
  96. Huang, T.; Dobrovolsky, D.; Paulk, J.; Yang, G.; Weisberg, E.L.; Doctor, Z.M.; Buckley, D.L.; Cho, J.H.; Ko, E.; Jang, J.; et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem. Biol. 2018, 25, 88–99.e6.
  97. Brand, M.; Jiang, B.; Bauer, S.; Donovan, K.A.; Liang, Y.; Wang, E.S.; Nowak, R.P.; Yuan, J.C.; Zhang, T.; Kwiatkowski, N.; et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 2019, 26, 300–306.
  98. Anderson, N.A.; Cryan, J.; Ahmed, A.; Dai, H.; McGonagle, G.A.; Rozier, C.; Benowitz, A.B. Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs. Bioorg. Med. Chem. Lett. 2020, 30, 127106.
  99. Steinebach, C.; Ng, Y.L.D.; Sosič, I.; Lee, C.-S.; Chen, S.; Lindner, S.; Vu, L.P.; Bricelj, A.; Haschemi, R.; Monschke, M.; et al. Systematic exploration of different E3 ubiquitin ligases: An approach towards potent and selective CDK6 degraders. Chem. Sci. 2020, 11, 3474–3486.
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