Development of targeted protein degradation therapeutics

PP Chamberlain, LG Hamann - Nature chemical biology, 2019 - nature.com
Targeted protein degradation as a therapeutic modality has seen dramatic progress and
massive investment in recent years because of the convergence of two key scientific …

Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders

J Yamamoto, T Ito, Y Yamaguchi… - Chemical Society Reviews, 2022 - pubs.rsc.org
Progress in strategies aimed at breaking down therapeutic target proteins has led to a
paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein …

Reversible ON-and OFF-switch chimeric antigen receptors controlled by lenalidomide

M Jan, I Scarfò, RC Larson, A Walker… - Science translational …, 2021 - science.org
Cell-based therapies are emerging as effective agents against cancer and other diseases.
As autonomous “living drugs,” these therapies lack precise control. Chimeric antigen …

Lessons in PROTAC design from selective degradation with a promiscuous warhead

DP Bondeson, BE Smith, GM Burslem… - Cell chemical …, 2018 - cell.com
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we
report a previously understudied benefit of small molecule proteolysis-targeting chimeras …

PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy

JM Kelm, DS Pandey, E Malin, H Kansou, S Arora… - Molecular Cancer, 2023 - Springer
Molecularly targeted cancer therapies substantially improve patient outcomes, although the
durability of their effectiveness can be limited. Resistance to these therapies is often related …

Plasticity in binding confers selectivity in ligand-induced protein degradation

RP Nowak, SL DeAngelo, D Buckley, Z He… - Nature chemical …, 2018 - nature.com
Heterobifunctional small-molecule degraders that induce protein degradation through ligase-
mediated ubiquitination have shown considerable promise as a new pharmacological …

Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN

QL Sievers, G Petzold, RD Bunker, A Renneville… - Science, 2018 - science.org
INTRODUCTION Thalidomide, lenalidomide, and pomalidomide are clinically approved
therapies for the treatment of multiple myeloma and other hematologic malignancies. These …

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

KA Donovan, J An, RP Nowak, JC Yuan, EC Fink… - elife, 2018 - elifesciences.org
In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of
thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and …

Exploring targeted degradation strategy for oncogenic KRASG12C

M Zeng, Y Xiong, N Safaee, RP Nowak… - Cell chemical …, 2020 - cell.com
KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung
cancers. Although it has been challenging to identify targeted therapies for cancers …

Delineating the role of cooperativity in the design of potent PROTACs for BTK

A Zorba, C Nguyen, Y Xu, J Starr… - Proceedings of the …, 2018 - National Acad Sciences
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that
simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination …