The rise of degrader drugs

Teng, Mingxing; Gray, Nathanael S.

doi:10.1016/j.chembiol.2023.06.020

Cited by 26 publications

(15 citation statements)

References 176 publications

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“…Targeted protein degradation (TPD) has arisen as a powerful approach for eliminating disease-causing proteins . Currently there are two major approaches for TPD: proteolysis targeting chimeras (PROTACs) and molecular glue degraders.…”

Section: Introductionmentioning

confidence: 99%

“…Targeted protein degradation (TPD) has arisen as a powerful approach for eliminating disease-causing proteins. 1 Currently there are two major approaches for TPD: proteolysis targeting chimeras (PROTACs) and molecular glue degraders. These approaches utilize either heterobifunctional or monovalent small-molecules to induce the proximity of E3 ubiquitin ligases with neo-substrates, resulting in their ubiquitination and subsequent degradation through the proteasome.…”

Section: ■ Introductionmentioning

confidence: 99%

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Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1

Meyers,

Cismoski,

Panidapu

et al. 2024

ACS Chem. Biol.

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Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4 adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1

Meyers,

Cismoski,

Panidapu

et al. 2024

ACS Chem. Biol.

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“…Further, because RaPID selects for protein binders rather than inhibitors, future investigations into the detailed binding mechanism and affinity of 41 against SIRT7 may reveal whether the peptide has potential as a starting point for the development of targeted protein degraders. [41]…”

Section: Methodsmentioning

confidence: 99%

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Bolding,

Nielsen,

Jensen

et al. 2023

Angew Chem Int Ed

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The sirtuins are NAD+‐dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε‐N‐acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small‐angle X‐ray scattering, reveal SIRT7 to be a monomeric enzyme with low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism‐based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA‐display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause increase in the acetylation H3K18.

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“…In recent years, induced protein degradation using the proteolysis targeting chimera (PROTAC) technology has become a very attractive strategy for the development of a completely new type of therapies for the treatment of human cancers. − To date, more than 20 PROTAC degraders have been advanced into clinical development, and promising clinical data have been reported for advanced PROTAC degraders such as ARV-110 (an androgen receptor PROTAC degrader) and ARV-471 (an estrogen receptor PROTAC degrader). , While potent PROTAC degraders of CBP/p300 such as dCBP-1, JQAD1, and JET-209 (Figure ) have been reported previously, − none of them are orally active. Because PROTAC degraders consist of two small-molecule ligands, joined together by a linker, they typically have molecular weights of 800–1200, much higher than traditional oral drug molecules.…”

Section: Introductionmentioning

confidence: 99%

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression

Chen,

Wang,

et al. 2024

J. Med. Chem.

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CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC 50 ≤ 0.03 nM and D max > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3−3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

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The rise of degrader drugs

Cited by 26 publications

References 176 publications

Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1

Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression

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