Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase

被引:18
作者
Rana, Sandeep [1 ]
Mallareddy, Jayapal Reddy [2 ]
Singh, Sarbjit [2 ]
Boghean, Lidia [2 ]
Natarajan, Amarnath [2 ,3 ,4 ,5 ]
机构
[1] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA
[2] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
[3] Pharmaceut Sci & Univ Nebraska Med Ctr, Omaha, NE 68198 USA
[4] Univ Nebraska Med Ctr, Genet Cell Biol & Anat, Omaha, NE 68198 USA
[5] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA
关键词
kinase; CDK; cancer; PROTAC; molecular glue; E3 UBIQUITIN LIGASE; CELL-CYCLE; SELECTIVE DEGRADATION; STRUCTURAL BASIS; HIGHLY POTENT; BREAST-CANCER; IMMUNOMODULATORY DRUGS; SYNTHETIC LETHALITY; RBM39; RECRUITMENT; CDK9;
D O I
10.3390/cancers13215506
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary:& nbsp;Cyclin-dependent kinases (CDKs) are rich and viable therapeutic targets for various cancers. The emergence of event-driven pharmacology as an alternative to occupancy-driven pharmacology has begun to address the challenges associated with selectively targeting CDKs. In this review article, we summarize the CDK inhibitors that are currently in clinical trials. In addition, we provide an overview of PROTAC- and molecular glue-based strategies to modulate CDK function.& nbsp;The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule-protein interactions. On the other hand, Molecular glues function by converting the target protein into a "neo-substrate " for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.
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页数:21
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共 152 条
  • [111] Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma
    Quach, H.
    Ritchie, D.
    Stewart, A. K.
    Neeson, P.
    Harrison, S.
    Smyth, M. J.
    Prince, H. M.
    [J]. LEUKEMIA, 2010, 24 (01) : 22 - 32
  • [112] Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma
    Rader, JulieAnn
    Russell, Mike R.
    Hart, Lori S.
    Nakazawa, Michael S.
    Belcastro, Lili T.
    Martinez, Daniel
    Li, Yimei
    Carpenter, Erica L.
    Attiyeh, Edward F.
    Diskin, Sharon J.
    Kim, Sunkyu
    Parasuraman, Sudha
    Caponigro, Giordano
    Schnepp, Robert W.
    Wood, Andrew C.
    Pawel, Bruce
    Cole, Kristina A.
    Maris, John M.
    [J]. CLINICAL CANCER RESEARCH, 2013, 19 (22) : 6173 - 6182
  • [113] Targeting CDK9 for treatment of colorectal cancer
    Rahaman, Muhammed H.
    Lam, Frankie
    Zhong, Longjin
    Teo, Theodosia
    Adams, Julian
    Yu, Mingfeng
    Milne, Robert W.
    Pepper, Chris
    Lokman, Noor A.
    Ricciardelli, Carmela
    Oehler, Martin K.
    Wang, Shudong
    [J]. MOLECULAR ONCOLOGY, 2019, 13 (10) : 2178 - 2193
  • [114] Small molecule induced polymerization of BCL6 facilitates SIAH1 mediated degradation
    Rana, Sandeep
    Natarajan, Amarnath
    [J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2021, 6 (01)
  • [115] Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK
    Rana, Sandeep
    Kour, Smit
    Sonawane, Yogesh A.
    Robb, Caroline M.
    Contreras, Jacob I.
    Kizhake, Smitha
    Zahid, Muhammad
    Karpf, Adam R.
    Natarajan, Amarnath
    [J]. CHEMICAL BIOLOGY & DRUG DESIGN, 2020, 96 (02) : 773 - 784
  • [116] Selective degradation of CDK6 by a palbociclib based PROTAC
    Rana, Sandeep
    Bendjennat, Mourad
    Kour, Smit
    King, Hannah M.
    Kizhake, Smitha
    Zahid, Muhammad
    Natarajan, Amarnath
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2019, 29 (11) : 1375 - 1379
  • [117] Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy
    Rana, Sandeep
    Sonawane, Yogesh A.
    Taylor, Margaret A.
    Kizhake, Smitha
    Zahid, Muhammad
    Natarajan, Amarnath
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (23-24) : 3736 - 3740
  • [118] Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy
    Robb, Caroline M.
    Kour, Smit
    Contreras, Jacob I.
    Agarwal, Ekta
    Barger, Carter J.
    Rana, Sandeep
    Sonawane, Yogesh
    Neilsen, Beth K.
    Taylor, Margaret
    Kizhake, Smitha
    Thakare, Rhishikesh N.
    Chowdhury, Sanjib
    Wang, Jing
    Black, Jennifer D.
    Hollingsworth, Michael A.
    Brattain, Michael G.
    Natarajan, Amarnath
    [J]. ONCOTARGET, 2018, 9 (04) : 5216 - 5232
  • [119] Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)
    Robb, Caroline M.
    Contreras, Jacob I.
    Kour, Smit
    Taylor, Margaret A.
    Abid, Mohammad
    Sonawane, Yogesh A.
    Zahid, Muhammad
    Murry, Daryl J.
    Natarajan, Amarnath
    Rana, Sandeep
    [J]. CHEMICAL COMMUNICATIONS, 2017, 53 (54) : 7577 - 7580
  • [120] Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update
    Roskoski, Robert, Jr.
    [J]. PHARMACOLOGICAL RESEARCH, 2021, 165