Induced protein degradation: an emerging drug discovery paradigm
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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TL;DR: In this paper, the authors define a new Begriff, der neuartige Peptidgeruststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartiche Weise eingesetzte, klassische niedermolekular Verbindungen berbuckichtigt.
Abstract: Unsere sich stetig erweiternden Kenntnisse uber biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation moglicherweise neuartige Therapiemoglichkeiten fur viele Krankheiten erschliest. Diese Angriffspunkte umfassen insbesondere Protein-Protein- und Protein-Nukleinsaure-Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitaten werden daher benotigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitaten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgeruststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berucksichtigt. Wir stellen die reprasentativsten Beispiele dieser Modalitaten vor, die auf grose Bindungsoberflachen, wie sie in Protein-Protein-Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgange abzielen.
30 citations
TL;DR: Utility of engineered E3 ligases to elucidate mechanisms underlying ubiquitin regulation of membrane proteins, and to achieve effective post-translational functional knockdown of ion channels are illustrated.
Abstract: Cells are surrounded by a membrane that separates the outside of the cell from its inside. Proteins called ion channels are embedded within this membrane and allow charged ions to move in and out of the cell. The movement of ions generates electrical currents that are essential for many processes that keep us alive, including our heartbeat and the activity within our brain. Like many other proteins, newly made ion channels undergo several steps before they mature and become active. Cells destroy any proteins that do not mature properly, as well as those that become damaged or are simply no longer needed. A small protein called ubiquitin helps to mark such unwanted proteins for destruction. Enzymes known as E3 ligases attach ubiquitin to target proteins in a process known as ubiquitination. This process regulates both the quality and amount of proteins within cells. To understand the role of a particular protein, it is often necessary to remove it from the cell and then examine the consequences. In the past, researchers have harnessed the ubiquitin system to remove many kinds of proteins, but this approach had not previously been used to target an ion channel. Now, Kanner et al. set out to selectively eliminate ion channels via targeted ubiquitination. The experiments showed that previous approaches that could destroy proteins within the cell were not effective against ion channels. Kanner et al. then engineered a particular E3 ligase so that it could selectively attach ubiquitin to the desired ion channels. This approach successfully prevented the channels from reaching the cell membrane, thereby silencing the electrical currents that they normally generate. Additionally, a new tool was developed to stop ion channels in their tracks, essentially with a flip of a chemical switch. Kanner et al. then used this approach to manipulate ion channels in a highly controlled manner, within their normal environment of heart muscle cells. These new approaches form a toolset that scientists can now exploit to study diverse ion channels. In the future, the toolkit could potentially be used to develop treatments for disorders such as epilepsy, chronic pain, and irregular heartbeats, where too many channels are active or present at the cell membrane.
30 citations
Cites background from "Induced protein degradation: an eme..."
...Furthermore, a chemical strategy has been developed that utilizes hetero-bivalent small molecules referred to as PROTACS (proteolysis-targeting chimeras) to bridge endogenous substrates to endogenous ubiquitin ligases (Schneekloth et al., 2004; Lai and Crews, 2017)....
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TL;DR: The current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years is examined.
Abstract: Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Several noteworthy advances have been made, among which the development of targeted therapies is the most significant. Monoclonal antibodies and antibody-small molecule conjugates have emerged as a worthwhile approach to improve drug selectivity and reduce adverse effects, which are the main challenges in cancer drug discovery. This review will examine the current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years. Breakthrough discoveries will be highlighted along with the medicinal chemistry strategies used throughout the discovery process. In addition, this review will provide perspectives and updates on the discovery of novel molecular targets as well as drugs with innovative mechanisms of action.
30 citations
TL;DR: Theis review will aim to critically evaluate the different approaches and principles emerging for targted protein degradation, some of which would be difficult to drug using conventional approaches.
30 citations
TL;DR: Both well-trod and less familiar versions of the interface between proteostasis and sterol regulation are described and some underlying ideas with broad biological and clinical applicability are suggested.
Abstract: In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation Both individual enzymes and transcriptional networks are controlled to meet changing needs of the many sterol pathway products Regulation is tailored by evolution to match regulatory constraints, which can be very different in distinct species Nevertheless, a broadly conserved feature of many aspects of sterol regulation is employment of proteostasis mechanisms to bring about control of individual proteins Proteostasis is the set of processes that maintain homeostasis of a dynamic proteome Proteostasis includes protein quality control pathways for the detection, and then the correction or destruction, of the many misfolded proteins that arise as an unavoidable feature of protein-based life Protein quality control displays not only the remarkable breadth needed to manage the wide variety of client molecules, but also extreme specificity toward the misfolded variants of a given protein These features are amena
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References
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
14,026 citations
TL;DR: This study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
Abstract: Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
12,865 citations
TL;DR: The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage as discussed by the authors.
Abstract: Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
12,265 citations
01 Feb 2013
TL;DR: Two different type II CRISPR/Cas systems are engineered and it is demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
Abstract: Genome Editing Clustered regularly interspaced short palindromic repeats (CRISPR) function as part of an adaptive immune system in a range of prokaryotes: Invading phage and plasmid DNA is targeted for cleavage by complementary CRISPR RNAs (crRNAs) bound to a CRISPR-associated endonuclease (see the Perspective by van der Oost). Cong et al. (p. 819, published online 3 January) and Mali et al. (p. 823, published online 3 January) adapted this defense system to function as a genome editing tool in eukaryotic cells. A bacterial genome defense system is adapted to function as a genome-editing tool in mammalian cells. [Also see Perspective by van der Oost] Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
10,746 citations
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
6,417 citations