Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform

Guo, Le; Liu, Jin; Nie, Xueqing; Wang, Taobo; Ma, Zewei; Yin, Dan; Tang, Weiping

doi:10.1016/j.bmcl.2022.128982

Cited by 8 publications

(3 citation statements)

References 41 publications

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“…We designed the CARM1 PROTAC based on TP-064, a CARM1 small-molecule inhibitor because TP-064 has a strong binding affinity and high selectivity for CARM1 . To quickly identify the appropriate E3 ubiquitin ligase and the approximate linker length, we decided to utilize our Rapid-TAC platform to generate the first set of PROTACs by coupling a hydrazide-containing CARM1 inhibitor with the aldehyde group in our preassembled PROTAC library. − After examining the crystal structure of CARM1 in complex with TP-064, the hydrazide moiety was placed on the para position of the terminal benzene, which is one of the solvent-exposed regions (Figure ). Compound 1 , TP-064 hydrazide derivative, was then prepared.…”

Section: Resultsmentioning

confidence: 99%

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders

Xie,

Bacabac,

et al. 2023

J. Med. Chem.

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Section: Resultsmentioning

confidence: 99%

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders

Xie,

Bacabac,

et al. 2023

J. Med. Chem.

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“…MGs often have been discovered by serendipity, while few rational discovery strategies are being developed 15,31 . Although platforms for rapid synthesis of PROTACs were reported, pipelines for MGs rapid development were rarely described [32][33][34] . Here, we describe a convenient D2B approach to discover MGs, combining automated miniaturized synthetic chemistry together with a phenotypic screening.…”

Section: Discussionmentioning

confidence: 99%

Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

Wang,

Shaabani,

Gao

et al. 2023

Nat Commun

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Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a direct-to-biology (D2B) approach for accelerated discovery of MGs. In this platform, automated, high throughput, and nano scale synthesis of hundreds of pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification of potent CRBN-acting MGs. The small molecules were further validated by degradation profiling and anti-cancer activity. This revealed E14 as a potent MG degrader targeting IKZF1/3, GSPT1 and 2 with profound effects on a panel of cancer cells. In a more generalized view, integration of automated, nanoscale synthesis with phenotypic assays has the potential to accelerate MGs discovery.

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“…Le Guo et al reported on the Rapid-Tac platform. 93 By introducing hydrazide groups into POI ligands and reacting quickly with preestablished VHL and CRBN ligand libraries containing acetaldehyde functional groups and various linkers, they could prepare dozens of compounds in one or two days. After that, these PROTACs were directly used for screening at the cellular level, and the hydrolytic hydrazide structure of the most active compounds was replaced Some researchers try to avoid the heavy work of linker optimization directly.…”

Section: Advanced Synthetic Strategiesmentioning

confidence: 99%

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Zhao

Chen

Huang

et al. 2023

Interdisciplinary Medicine

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Proteolysis-targeting chimeras (PROTACs) is a targeted protein degradation (TPD) technique effected by hijacking the ubiquitin-proteasome system (UPS) of the cells. A PROTAC molecule specifically binds to its protein of interest (POI) and recruits an E3 ligase to assemble a ternary complex. The POI was subsequently ubiquitinated, followed by being degraded by proteasomes. After 20 years of development, PROTAC technology has made a significant progress, and quite some candidates have entered clinical trials. Along with the excitement of realizing that PROTAC technology can develop therapeutics toward those traditionally believed "undruggable" targets; there are still unmet demands in PROTAC design, screening, and intracellular availability. PROTAC technology is rapidly advancing from employing traditional medicinal chemistry methodologies to integrating state-of-the-art chemical biology technologies, becoming a typical example of interdisciplinary medicine. This review summarizes the progress made in PROTAC technology in recent years, including expanding new targets, developing dual-target PROTACs, rational design and screening strategies, regulatory activation, targeted delivery, and developing biological macromolecule-contained PROTACs.

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Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform

Cited by 8 publications

References 41 publications

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders

Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

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