scholarly journals A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands

2020 ◽  
Vol 295 (45) ◽  
pp. 15280-15291
Author(s):  
Bomie Han
Keyword(s):  
Drug Development ◽  
Protein Degradation ◽  
Ternary Complex ◽  
Quantitative Measurement ◽  
Degradation Mechanism ◽  
Equilibrium Constants ◽  
Target Engagement ◽  
Promising Area ◽  
Analytical Tools ◽  
First Time

Small molecule–induced targeted protein degradation by heterobifunctional ligands or molecular glues represents a new modality in drug development, allowing development of therapeutic agents for targets previously considered undruggable. Successful target engagement requires the formation of a ternary complex (TC) when the ligand brings its target protein in contact with an E3 ubiquitin ligase. Unlike traditional drugs, where target engagement can be described by a simple bimolecular equilibrium equation, similar mathematical tools are currently not available to describe TC formation in a universal manner. This current limitation substantially increases the challenges of developing drugs with targeted protein degradation mechanism. In this article, I provide a full, exact, and universal mathematical description of the TC system at equilibrium for the first time. I have also constructed a comprehensive suite of mathematical tools for quantitative measurement of target engagement and equilibrium constants from experimental data. Mechanistic explanations are provided for many common challenges associated with developing this type of therapeutic agent. Insights from these analyses provide testable hypotheses and grant direction to drug development efforts in this promising area. The mathematical and analytical tools described in this article may also have broader applications in other areas of biology and chemistry in which ternary complexes are observed.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

2021 ◽  
Author(s):  
Adam J. Schwarz
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Development Program ◽  
Imaging Biomarkers ◽  
Common Disease ◽  
Structural Imaging ◽  
Target Engagement ◽  
Pharmacodynamic Effect

AbstractImaging biomarkers play a wide-ranging role in clinical trials for neurological disorders. This includes selecting the appropriate trial participants, establishing target engagement and mechanism-related pharmacodynamic effect, monitoring safety, and providing evidence of disease modification. In the early stages of clinical drug development, evidence of target engagement and/or downstream pharmacodynamic effect—especially with a clear relationship to dose—can provide confidence that the therapeutic candidate should be advanced to larger and more expensive trials, and can inform the selection of the dose(s) to be further tested, i.e., to “de-risk” the drug development program. In these later-phase trials, evidence that the therapeutic candidate is altering disease-related biomarkers can provide important evidence that the clinical benefit of the compound (if observed) is grounded in meaningful biological changes. The interpretation of disease-related imaging markers, and comparability across different trials and imaging tools, is greatly improved when standardized outcome measures are defined. This standardization should not impinge on scientific advances in the imaging tools per se but provides a common language in which the results generated by these tools are expressed. PET markers of pathological protein aggregates and structural imaging of brain atrophy are common disease-related elements across many neurological disorders. However, PET tracers for pathologies beyond amyloid β and tau are needed, and the interpretability of structural imaging can be enhanced by some simple considerations to guard against the possible confound of pseudo-atrophy. Learnings from much-studied conditions such as Alzheimer’s disease and multiple sclerosis will be beneficial as the field embraces rarer diseases.

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

2021 ◽  
Author(s):  
Raphael R. Steimbach ◽  
Corey J. Herbst-Gervasoni ◽  
Glynis Klinke ◽  
Magalie Géraldy ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Target Engagement ◽  
Target Validation ◽  
Chemical Probes ◽  
Combination Cancer Therapy ◽  
Selective Chemical ◽  
First Time ◽  
Double Digit ◽  
Novel Therapeutic ◽  
Thermal Shift

We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.

scholarly journals Trivalent PROTACs enhance protein degradation through cooperativity and avidity

2020 ◽  
Author(s):  
Alessio Ciulli ◽  
Satomi Imaide ◽  
Kristin Riching ◽  
Vesna Vetma ◽  
Claire Whitworth ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Conformational Changes ◽  
Ternary Complex ◽  
High Avidity ◽  
Proof Of Concept ◽  
Complex Interactions ◽  
Anti Cancer ◽  
Sufficient Stability ◽  
Bet Protein ◽  
Molecular Recognition Features

Abstract Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.

Solvent extraction studies of the system 64Cu/Htta/topo and the role of the metal complexes involved

1970 ◽  
Vol 23 (12) ◽  
pp. 2413
Author(s):  
EB Jacobs ◽  
WR Walker
Keyword(s):  
Solvent Extraction ◽  
Metal Complexes ◽  
Organic Phase ◽  
Ternary Complex ◽  
Equilibrium Constants ◽  
Synergistic Extraction ◽  
Back Extraction

Solvent extraction studies have been carried out on the system Cu/Htta/topo (Htta = thenoyltrifluoroacetone; topo = tri-n-octylphosphine oxide) with benzene as the organic phase. Using 64Cu as a tracer, equilibrium constants have been evaluated and compared with data obtained from the back-extraction of the labelled ternary complex 64Cu(tta)2(topo). The solubilities of binary and secondary complexes that are involved in synergistic extraction have also been measured.

Medicinal Inula Species: Phytochemistry, Biosynthesis, and Bioactivities

2021 ◽  
pp. 1-44
Author(s):  
Cheng-Peng Sun ◽  
Zi-Li Jia ◽  
Xiao-Kui Huo ◽  
Xiang-Ge Tian ◽  
Lei Feng ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Drug Development ◽  
Scientific Basis ◽  
Pharmacological Properties ◽  
Pharmacological Activities ◽  
Traditional Medicines ◽  
The World ◽  
Phytochemical Constituents ◽  
New Drug Development ◽  
First Time

As a genus of the Asteraceae, Inula is widely distributed all over the world, and several of them are being used in traditional medicines. A number of metabolites were isolated from Inula species, and some of these have shown to possess ranges of pharmacological activities. The genus Inula contains abundant sesquiterpenoids, such as eudesmanes, xanthanes, and sesquiterpenoid dimers and trimers. In addition, other types of terpenoids, flavonoids, and lignins also exist in the genus Inula. Since 2010, more than 300 new secondary metabolites, including several known natural products that were isolated for the first time from the genus Inula. Most of them exhibited potential bioactivities in various diseases. The review aimed to summarize the advance of recent researches (2010–2020) on phytochemical constituents, biosynthesis, and pharmacological properties of the genus Inula for providing a scientific basis and supporting its application and exploitation for new drug development.

scholarly journals Enhancement of the photocatalytic synchronous removal of Cr(vi) and RhB over RP-modified flower-like SnS2

2020 ◽  
Vol 2 (9) ◽  
pp. 4220-4228
Author(s):  
Xue Bai ◽  
Yanyan Du ◽  
Wenhua Xue ◽  
Xiaoyun Hu ◽  
Jun Fan ◽  
...  
Keyword(s):  
Photocatalytic Degradation ◽  
Degradation Mechanism ◽  
Photocatalytic Degradation Mechanism ◽  
First Time

RP/SnS2 nanocomposite as photocatalyst was fabricated for the first time, exhibiting remarkable activity to synchronous removal of Cr(vi) and RhB. The possible pathway of carriers and photocatalytic degradation mechanism was systematically studied.

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