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Journal ArticleDOI

Induced protein degradation: an emerging drug discovery paradigm

01 Feb 2017-Nature Reviews Drug Discovery (Nature Research)-Vol. 16, Iss: 2, pp 101-114
TL;DR: Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
Abstract: Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.

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Citations
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Journal ArticleDOI
TL;DR: The results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
Abstract: Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

646 citations

Journal ArticleDOI
TL;DR: An overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors are provided.
Abstract: Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.

620 citations

Journal ArticleDOI
TL;DR: Four scientists working in the 'undruggable' cancer research field are asked for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.
Abstract: The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and therefore more appropriate terms might be 'difficult to drug' or 'yet to be drugged'. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.

529 citations

Journal ArticleDOI
TL;DR: This Review discusses the various approaches that are being explored to target transcription factors in cancer, with many of the inhibitors developed from such approaches now advancing to early clinical trials.
Abstract: Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor-cofactor protein-protein interactions, inhibition of transcription factor-DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.

409 citations

Journal ArticleDOI
TL;DR: Opportunities for the expansion of the medicinal chemists' synthetic toolbox are highlighted to enable enhanced impact of new methodologies in future drug discovery.
Abstract: The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

348 citations

References
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Journal ArticleDOI
TL;DR: Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models.
Abstract: Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.

153 citations

Journal ArticleDOI
TL;DR: Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER, which was associated with early progression in patients with metastatic breast cancer.
Abstract: It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) downregulator, is sufficient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/computed tomography (PET/CT) at baseline (Scan 1), day 28 (Scan 2) and day 84 (Scan 3) to monitor tumor [18F]fluoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefined as < 75% decrease in median tumor FES uptake and a residual standardized uptake value (SUVmax) ≥ 1.5. In total 131 FES-positive lesions were identified (median SUVmax of 2.9, range 1.7-6.5). The median change in patients during fulvestrant treatment was -85% at Scan 2, but varied widely (-99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at Scan 2 in 6 (38%) of the 16 patients, which was associated with early progression.

152 citations

Journal ArticleDOI
01 Mar 1999
TL;DR: Fomivirsen (ISIS 2922) is an antisense oligonucleotide which specifically inhibits replication of human cytomegalovirus (CGV).
Abstract: ▴ Fomivirsen (ISIS 2922) is an antisense oligonucleotide which specifically inhibits replication of human cytomegalovirus. It achieves this by binding to complementary sequences on messenger RNA transcribed from the major immediate-early transcriptional unit of the virus. It is being developed for the treatment of cytomegalovirus retinitis. ▴ Mean maximum retinal concentrations of fomivirsen occurred ∼2 days after a single intravitreal injection in monkeys. The elimination half-life of fomivirsen (after a single 115μg dose) in monkey retina was 78 hours. ▴ Fomivirsen, administered as an intravitreal injection, significantly delayed progression of cytomegalovirus retinitis in patients with AIDS in preliminary clinical trials. In 18 patients with newly diagnosed, unilateral, peripheral cytomegalovirus retinitis treated with fomivirsen 165μg once weekly for 3 weeks, then 165μg every second week, the median time to disease progression was significantly longer than in 10 patients in whom fomivirsen treatment was deferred until early disease progression (71 vs 14 days). ▴ In patients with advanced, refractory, sight-threatening disease, treatment with fomivirsen 330μg once weekly for 3 weeks and then 330μg every 2 weeks (n = 34) or 330μg on days 1 and 15 and then monthly (n = 20) significantly delayed disease progression. The interpolated median time to disease progression was 90 days in both treatment groups. ▴ The most common adverse events reported in clinical trials of fomivirsen were increased intraocular pressure and mild to moderate intraocular inflammation. These events were generally transient or reversible with topical steroid treatment.

150 citations

Journal ArticleDOI
TL;DR: It is demonstrated that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3 dependent cancer cell lines, and suggests that small molecules will be capable of perturbing the biological function of She3 and the approximately 60 other pseudokinases found in human cells.
Abstract: The use of ATP competitive kinase inhibitors against the pseudokinase Her3 has been largely unsuccessful. Hydrophobic tagging of a covalent kinase inhibitor promotes Her3 degradation and prevents productive dimerization and signaling.

148 citations

Journal ArticleDOI
TL;DR: The generation of a novel class of selective androgen receptor degraders (SARDs) is described to address this resistance mechanism and suggests that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.
Abstract: Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.

139 citations

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