A comprehensive review of BET-targeting PROTACs for cancer therapy

Zhou, Xiaoli; Zhao, Fang; Xu, Yan; Guan, Yu; Tong, Yu; Zhang, Yizhe; Duan, Ying-Chao; Zhao, Yuan

doi:10.1016/j.bmc.2022.117033

Cited by 15 publications

(27 citation statements)

References 124 publications

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“…1 H NMR (400 MHz, CD3OD-d4) δ 7.91 (d, J = 8.4, 2H), 7.77-7.72 (m, 4H), 7.56 (d, J = 8.2 Hz, 2H), 4.64 (t, J = 7.2 Hz, 1H), 4.50 (s, 1H), 3.78 (s, 3H), 3.56 (d, J = 7.2 Hz, 2H), 3.43 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.47 (s, 3H), 1.75 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13…”

Section: Synthesis Of Compound 4bmentioning

confidence: 99%

“…1 H NMR (400 MHz, CD3OD-d4) δ 7.78 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 6.4 Hz, 2H), 4.29 (s, 2H), 2.5 (s, 3H), 1.42 (s, 9H). 13…”

Section: Tert-butyl (4-(n-methylsulfamoyl)benzyl)carbamate (4c-4)mentioning

confidence: 99%

“…Compound 5 was synthesized according to the same procedure with compound 1 using 5a-1 28 13 C NMR (101 MHz, CD3OD-d4) δ 173.09, 145. 37, 139.50, 131.96, 128.78, 128.63, 1128.25, 123.24, 123.18, 120.95, 119.10, 116.78, 106.29, 72.05, 71.44, 71.42, 71.36, 71.23, 70.97, 51.68, 42.…”

Section: Synthesis Of Compoundmentioning

confidence: 99%

“…13 C NMR (126 MHz, acetone-d6) δ 167.36, 146.43, 142.49, 138.64, 135.15, 132.71, 132.44, 129.83, 129.75, 128.67, 128.30, 128.13, 127.90, 123.57, 121.37, 120.96, 117.56, 86.73, 43.43, 21.34, 18.21. LC-MS, ESI + , m/z 459.1 [M+H] + .…”

mentioning

confidence: 99%

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Targeted protein degradation via intramolecular bivalent glues

Hsia

Hinterndorfer

Cowan

et al. 2023

Preprint

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Targeted protein degradation is a drug modality represented by compounds that recruit a target to an E3 ubiquitin ligase to promote target ubiquitination and proteasomal degradation. Historically, the field distinguishes monovalent degraders from bifunctional degraders (PROTACs) that connect target and ligase via separate binding ligands joined via a linker1-4. Here, we elucidate the mechanism of action of a PROTAC-like degrader of the transcriptional coactivator BRD4, composed of a BRD4 ligand linked to a ligand for the E3 ligase CRL4DCAF15. Using orthogonal CRISPR/Cas9 screens we identify the degrader activity is independent of DCAF15, and relies on a different CRL4 substrate receptor, DCAF16. We demonstrate an intrinsic affinity between BRD4 and DCAF16, which is dependent on the tandem bromodomains of BRD4 and further increased by the degrader without physically engaging DCAF16 in isolation. Structural characterization of the resulting ternary complex reveals both BRD4 bromodomains are bivalently engaged in cis by the degrader and are bound to DCAF16 through several interfacial BRD4-DCAF16 and degrader-DCAF16 contacts. Our findings demonstrate that intramolecularly bridging domains can confer glue-type stabilization of intrinsic target-E3 interactions, and we propose this as a general strategy to modulate the surface topology of target proteins to nucleate co-opting of E3 ligases or other cellular effector proteins for effective proximity-based pharmacology.

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Section: Synthesis Of Compound 4bmentioning

confidence: 99%

“…1 H NMR (400 MHz, CD3OD-d4) δ 7.78 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 6.4 Hz, 2H), 4.29 (s, 2H), 2.5 (s, 3H), 1.42 (s, 9H). 13…”

Section: Tert-butyl (4-(n-methylsulfamoyl)benzyl)carbamate (4c-4)mentioning

confidence: 99%

Section: Synthesis Of Compoundmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeted protein degradation via intramolecular bivalent glues

Hsia

Hinterndorfer

Cowan

et al. 2023

Preprint

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“…The BRD2 selective inhibitor ABBV-744 is already in clinical trials for the treatment of acute myeloid leukemia [55]. The first BET PROTACs were reported in 2015 [27], and degraders are increasingly being identified [56,57]. However, the lack of intra-BET selectivity has limited their application for target verification and may also induce adverse effects or toxicity.…”

Section: Protac Drugs Based On Small Molecules Discovered By Molecula...mentioning

confidence: 99%

Computational strategies for PROTAC drug discovery

Wang

Leung

2023

Acta Materia Medica

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Proteolysis-targeting chimeras (PROTACs), a novel targeted protein degradation technology for potential clinical drug discovery, is composed of a protein-targeting ligand covalently linked to an E3 ligase ligand. Through recruiting E3 ligase to target proteins, PROTACs elicit ubiquitination and subsequent degradation of targets via the ubiquitin-proteasome system. In the past few decades, molecular docking and virtual screening have emerged as an efficient strategy in drug discovery for identifying compounds from a large database of chemical structures. For PROTACs, molecular docking accurately simulates the protein-PROTAC-E3 ternary complex, thus greatly accelerating structure-activity-relationship analysis, and improving ligand affinity and selectivity. In this review, we summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery. To date, approximately nine target proteins and twelve PROTACs have been successfully developed through molecular docking and virtual screening. Finally, the potential challenges of molecular docking and virtual screening-based PROTACs are discussed.

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Solid‐Phase Synthesis of PROTACs and SNIPERs on Backbone Amide Linked (BAL) Resin

Hales,

Thompson

2023

Chemistry A European J

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Developing straightforward but flexible approaches to PROTAC synthesis that can incorporate the structural elements of emerging designs can improve the quality and efficiency of PROTAC development. Solid‐phase approaches could offer many advantages over conventional PROTAC synthesis if diverse chemistries and topographies can be incorporated. We have exploited the backbone‐amide‐linked (BAL) resin to employ an array of solid‐phase organic reactions, providing access to VHL‐ and IAP‐targeting degraders using the BRD4‐targeting JQ1 conjugates as examples.

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A comprehensive review of BET-targeting PROTACs for cancer therapy

Cited by 15 publications

References 124 publications

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation via intramolecular bivalent glues

Computational strategies for PROTAC drug discovery

Solid‐Phase Synthesis of PROTACs and SNIPERs on Backbone Amide Linked (BAL) Resin

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