Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation

Tokarski, Robert J.; Sharpe, Chia M.; Huntsman, Andrew C.; Mize, Brittney K.; Ayinde, Oluwatosin R.; Stahl, Emily H.; Lerma, James R.; Reed, Andrew; Carmichael, Bridget; Muthusamy, Natarajan; Byrd, John C.; Fuchs, James R.

doi:10.1016/j.ejmech.2023.115342

Cited by 8 publications

(3 citation statements)

References 41 publications

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“…138 3 and 10 both are classical CDK9 inhibitors and show improved performance after linked with thalidomide, namely 84 and 85, respectively. 139 Because 3 have already got high potency, 84 attains even better potency, reaching a submicromolar IC 50 of 25 nM on MV4-11 cells in vitro. 140 Apart from the PROTACs mentioned above, several dual-target inhibitors are also employed in the degrader synthesis, as exemplified by PROTAC13 (86).…”

Section: Degradersmentioning

confidence: 99%

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

Zhang,

Shan,

Tang

et al. 2024

J. Med. Chem.

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CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure–activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

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Section: Degradersmentioning

confidence: 99%

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

Zhang,

Shan,

Tang

et al. 2024

J. Med. Chem.

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“…While a few oncogenic proteins have been successfully targeted by PROTACs in EOC models (Figure 2), there remains great potential for PROTACs characterized in other types of cancer to be developed in EOC. Some of the most prominent examples of these are PROTACs that target Poly ADP Ribose Polymerase 1 (PARP1) [56][57][58][59][60], Forkhead Box M1 (FOXM1) [61,62], c-Myc (MYC) [63], Epidermal Growth Factor Receptor (EGFR) [60,, and Cyclin Dependent Kinases (CDK) 2 [85][86][87][88][89] and 9 [22,[89][90][91][92][93][94][95][96][97]. We will discuss two of these new classes of PROTACs in detail below, those that target PARP1 and those that target FOXM1.…”

Section: Novel Potential Protac Targets In Eocmentioning

confidence: 99%

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

Vorderbruggen,

Velázquez-Martínez,

Natarajan

et al. 2024

IJMS

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Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents.

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“…Recently, we reported the synthesis of two series of CDK9 degraders that contained alkyl and amide linker moieties. 29 These degraders, which were based on the pan-CDK9 inhibitor AT7519 (1), 30 demonstrated that compounds of this type can selectively degrade CDK9 and illustrated the direct impact that the linker has on the overall physicochemical properties and in vitro activity of degraders containing the cereblon-recruiting ligands 4-hydroxy thalidomide and pomalidomide. While synthesizing these initial degraders, an alternative strategy utilizing click chemistry to rapidly assemble the linker region was also considered.…”

Section: T H Imentioning

confidence: 99%

Examination of the Impact of Triazole Position within Linkers on Solubility and Lipophilicity of a CDK9 Degrader Series

Ayinde

Sharpe

Stahl

et al. 2023

ACS Med. Chem. Lett.

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Optimization of degrader properties is often a challenge due to their beyond-rule-of-5 nature. Given the paucity of known E3 ligases and the often-limited choice of ligands with varied chemical structures for a given protein target, degrader linkers represent the best position within the chimeric molecules to modify their overall physicochemical properties. In this work, a series of AT7519-based CDK9 degraders was assembled using click chemistry, facilitating the tuning of aqueous solubility and lipophilicity while retaining their linker type and molecular weight. Using chromatographic logD and kinetic solubility experiments, we show that degraders with similar chemical constitution but varied position of the embedded triazole demonstrate different lipophilicity and aqueous solubility properties. Overall, this work highlights the impact of triazole placement on linker composition through application of click chemistry for degrader synthesis and its ability to be used to promote the achievement of favorable physicochemical properties.

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Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation

Cited by 8 publications

References 41 publications

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

Examination of the Impact of Triazole Position within Linkers on Solubility and Lipophilicity of a CDK9 Degrader Series

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