Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Steinebach, Christian; Ng, Yuen Lam Dora; Sosič, Izidor; Lee, Chih-Shia; Chen, Sirui; Lindner, Stefanie; Vu, Lan Phuong; Bricelj, Aleša; Haschemi, Reza; Monschke, Marius; Steinwarz, Elisabeth; Wagner, Karl; Bendas, Gerd; Luo, Ji; Gütschow, Michael; Krönke, Jan

doi:10.1039/d0sc00167h

Cited by 84 publications

(100 citation statements)

References 77 publications

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“…Recently, an increasing number of publications have emerged where the physical properties of PROTACs are accounted for in their design, or in the rationalisation of their efficacy [121][122][123][124]. Mares et al [125], developed a potent cIAP-recruiting PROTAC (82) for the degradation of RIPK2 containing a PEG linker (pDC 50 = 9.4 in THP-1 monocytes, Figure 17).…”

Section: Deg S _mentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

163

159

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PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

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Section: Deg S _mentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

163

159

View full text Add to dashboard Cite

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“…The authors compared BSJ‐03‐123 with their best compound and observed that, still in MM.1S cells, a recovering of CDK6 levels began after 24 h with BSJ‐03‐123, whereas CST651 and CST620 induced a persistent degradation of CDK6 even after 96 h. These compounds also showed very efficient degradation of this kinase in a broad range of different human and murine cancer cells. Moreover, after a washout step, BSJ‐03‐123 kept CDK6 protein levels below 50% for a maximum of 6 h while the two VHL compounds induced low and stable levels of CDK6 for up to 72 h. [ 100 ] This study confirmed that a CRBN‐based PROTAC is not the only way forward to access efficient degraders. Moreover, whereas the nature of the linker has one more time demonstrated a critical effect on the efficacy and selectivity of the PROTACs, the structure of the E3 UL recruiter could also play an important role in these fields.…”

Section: Serine‐threonine Kinases (Stks) Degradersmentioning

confidence: 53%

“…Thus, their inhibition could offer new ways to treat inflammatory or autoimmune diseases. Recently, several STKs were targeted using the PROTAC technology: the interleukin‐1 receptor‐associated kinase 4 (IRAK4), [ 94 ] the serum and glucocorticoid‐induced protein kinase 3 (SGK3), [ 95 ] the polo‐like kinase 1 (PLK1), [ 96 ] several members of the CDK family, [ 97–102 ] and the B isoform of the rapidly accelerated fribrosarcoma (BRAF). [ 103 ]…”

Section: Serine‐threonine Kinases (Stks) Degradersmentioning

confidence: 99%

“…CDKs 1, 2, 3, 4, and 6 are the major protein kinases of this subfamily involved in the cell cycle regulation, while CDKs 7, 8, 9, and 11 are key players in RNA processing. [ 122 ] Several PROTAC compounds were recently developed to degrade CDK9, [ 97 ] CDK6, [ 98,100 ] CDK4/6 (a dual PROTAC), [ 101 ] and CDK2. [ 102 ]…”

Section: Serine‐threonine Kinases (Stks) Degradersmentioning

confidence: 99%

“…employed four different E3 recruiters (CRBN, VHL, cIAP, and MDM2) for the design of potent and selective CDK6 PROTACs also using palbociclib as the POI recruiter. [ 100 ] These four series of PROTACs were tested to determine an optimal linker in each series. Within the CRBN series, compounds with shortest linkers (7 to 15 atoms) showed the best potency to degrade both CDK4 and CDK6 in the multiple myeloma cell line MM.1S.…”

Section: Serine‐threonine Kinases (Stks) Degradersmentioning

confidence: 99%

See 2 more Smart Citations

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Feral

Laconde

Amblard

et al. 2020

Advanced Therapeutics

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Since the development of the first protein kinase inhibitor in the early 1980s, followed by the FDA approval of imatinib in 2001, kinases are one of the most intensively pursued targets in current medicinal chemistry research. These proteins are overrepresented in various diseases such as cancer, inflammation or autoimmune pathologies and play important roles in their physiopathogenic processes. Despite the development and approval of numerous potent kinase inhibitors, drug resistance and off‐target side effects are commonly encountered with kinase inhibitors. Thus, development of novel strategies to overcome these problems is necessary. Since 2013, many research groups have proposed the conversion of potent kinase inhibitors into PROteolysis TArgeting Chimera (PROTAC) compounds and shared relevant and encouraging results using this new technology, which degrades proteins by employing the cellular machinery. Generally, this strategy brings enhancements in biological effects compared to the use of only the parent inhibitor. In this review article, recent findings related to the PROTAC technology applied to kinases are discussed, with a special focus on publications since 2018.

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Another structural correction for 1‐oxo‐1H‐phenalene‐2,3‐dicarbonitriles: Synthesis of a potent BCL‐2 inhibiting 7‐phenoxy derivative

Sosič

Gobec

Steinebach

et al. 2021

Archiv der Pharmazie

Self Cite

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Aromatic scaffolds are an important part of biologically active compounds and molecular probes used to study biochemical pathways and the involved targeted proteins of interest. 1‐Oxo‐1H‐phenalene‐2,3‐dicarbonitrile‐based compounds have been described as inhibitors of the BCL‐2 family of proteins, and this core structure represents numerous possibilities for modifications that could lead to improved inhibitory potencies. Many studies demonstrated intriguing characteristics of these compounds in terms of reactivity and, interestingly, some contradictory literature reports appeared about reaction outcomes to synthesize them. Here, we initially provide a condensed overview of transformations performed on the phenalene scaffold, followed by the resynthesis of a 6‐phenoxy‐substituted derivative. We show that the initial determination of this particular structure was wrong and provide two‐dimensional nuclear magnetic resonance (NMR) evidence to assign the structure properly. When preparing new derivatives using the same synthetic route, we observed 6‐ and 7‐substituted regioisomers. After confirming their structures by NMR experiments, the ability of these compounds to inhibit BCL‐2 was evaluated. The most potent 1‐oxo‐1H‐phenalene‐2,3‐dicarbonitrile derivatives inhibited BCL‐2 in the nanomolar range and showed double‐digit micromolar cytotoxicity against four different cancer cell lines.

show abstract

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Abstract: Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein.

Cited by 84 publications

References 77 publications

Current strategies for the design of PROTAC linkers: a critical review

Current strategies for the design of PROTAC linkers: a critical review

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Another structural correction for 1‐oxo‐1H‐phenalene‐2,3‐dicarbonitriles: Synthesis of a potent BCL‐2 inhibiting 7‐phenoxy derivative

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