Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity

Pillow, Thomas H.; Adhikari, Pragya; Blake, Robert A.; Chen, Jinhua; Rosario, Geoffrey Del; Deshmukh, Gauri; Figueroa, Isabel; Gascoigne, Karen E.; Kamath, Amrita V.; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Latifi, Brandon; Leipold, Douglas D.; Li, Chun Sing; Li, Ruina; Mulvihill, Melinda M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Sadowsky, Jack; Wai, John S.; Wang, Xinxin; Wu, Cong; Xu, Zijin; Yao, Hui; Yu, Shang‐Fan; Zhang, Donglu; Zang, Richard; Zhang, Hongyan; Zhou, Hao; Zhu, Xiaoyu; Dragovich, Peter S.

doi:10.1002/cmdc.201900497

Cited by 141 publications

(158 citation statements)

References 40 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…A deeper understanding of the stability of the TC will be crucial to achieve this, and may be quantified through techniques such as surface plasmon resonance (SPR), as recently demonstrated by Roy et al [55]. In particular, the researchers observed that TCs with long half-lives displayed enhanced cooperativities and more favourable degradation profiles in comparison to those with fast dissociation kinetics, a finding which has subsequently been validated by Pillow et al [165]. The use of biophysical techniques to monitor TC kinetics when optimising PROTAC linker chemistry may become more commonplace in future as a strategy to improve PROTAC potency and selectivity whilst mitigating the hook effect.…”

Section: Discussionmentioning

confidence: 92%

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

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 92%

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

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

View full text Add to dashboard Cite

show abstract

“…GNE-987 ( Fig. 2), containing a potent tetracyclic BRD4 inhibitor, exhibited extremely high activities in degradation of BRD4 and growth inhibition of acute myeloid leukemia EOL-1 cells in low pM levels [44]. Due to its poor pharmacokinetics (PK), GNE-987 was attached to an antibody of CLL1 (C-type lectin-like molecule-1) to form the conjugate CCL1-5 with good PK properties.…”

Section: Vhl-based Protacsmentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

View full text Add to dashboard Cite

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting~50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

show abstract

“…Although PROTAC technology was first described nearly 20 years ago 4 , there has been a dramatic increase in interest and activity catalysed by improvements in the embedded E3 ligase binders [5][6][7][8] which have delivered higher cell permeability. These improvements have increased cellular protein degradation potency of PROTACs from the high micromolar range to the low or even sub-nanomolar range [9][10][11][12] .…”

mentioning

confidence: 99%

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

et al. 2020

View full text Add to dashboard Cite

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

show abstract

Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity

Cited by 141 publications

References 40 publications

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

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

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Contact Info

Product

Resources

About