Small molecule inhibitors targeting the cancers DOI Creative Commons
Guihong Liu, Tao Chen, Xin Zhang

et al.

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Oct. 13, 2022

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.

Language: Английский

The evolving role of investigative toxicology in the pharmaceutical industry DOI Creative Commons
François Pognan, Mario Beilmann, Harrie C. M. Boonen

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(4), P. 317 - 335

Published: Feb. 13, 2023

For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects were carefully reported and used as basis to calculate safety margins for drug candidates. In recent years, however, technological advances have increasingly enabled researchers gain insights into toxicity mechanisms, supporting greater understanding of species relevance translatability humans, prediction events, mitigation side development biomarkers. Consequently, investigative (or mechanistic) has been gaining momentum is now key capability the pharmaceutical industry. Here, we provide an overview current status field using case studies discuss potential impact ongoing developments, based on survey toxicologists from 14 European-based medium-sized large companies. Investigative tools strategies are companies reduce safety-related attrition development. This Perspective article summarizes goals toxicology, highlights approaches discusses selected emerging technologies that improve safety-testing paradigm.

Language: Английский

Citations

138
Theranostic Fluorescent Probes DOI Creative Commons
Amit Sharma, Peter Verwilst, Mingle Li

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(5), P. 2699 - 2804

Published: Feb. 29, 2024

The ability to gain spatiotemporal information, and in some cases achieve control, the context of drug delivery makes theranostic fluorescent probes an attractive intensely investigated research topic. This interest is reflected steep rise publications on topic that have appeared over past decade. Theranostic probes, their various incarnations, generally comprise a fluorophore linked masked drug, which released as result certain stimuli, with both intrinsic extrinsic stimuli being reported. release then signaled by emergence signal. Importantly, use appropriate fluorophores has enabled not only this emerging fluorescence marker for but also provided modalities useful photodynamic, photothermal, sonodynamic therapeutic applications. In review we highlight recent work particular focus are activated tumor microenvironments. We summarize efforts develop other applications, such neurodegenerative diseases antibacterials. celebrates diversity designs reported date, from discrete small-molecule systems nanomaterials. Our aim provide insights into potential clinical impact still-emerging direction.

Language: Английский

Citations

138
Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy DOI
Kailin Yang, Ahmed Halima, Timothy A. Chan

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(9), P. 604 - 623

Published: June 16, 2023

Language: Английский

Citations

121
Payload diversification: a key step in the development of antibody–drug conjugates DOI Creative Commons

Louise Conilh,

Lenka Sadílková,

Warren Viricel

et al.

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Jan. 17, 2023

Abstract Antibody–drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity monoclonal antibodies with potency payload consisting cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at forefront ADC development. The recent approval clinical success trastuzumab deruxtecan (Enhertu ® ) sacituzumab govitecan (Trodelvy ), two topoisomerase 1 inhibitor-based ADCs, has shown potential conjugating unconventional payloads differentiated mechanisms action. Among future developments in field, diversification expected to play key role as illustrated by growing number preclinical stage payload-conjugated ADCs. This review presents comprehensive overview validated, forgotten newly developed different

Language: Английский

Citations

119
Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic DOI Creative Commons
Janet M. Sasso,

Rumiana Tenchov,

Dasheng Wang

et al.

Biochemistry, Journal Year: 2022, Volume and Issue: 62(3), P. 601 - 623

Published: July 20, 2022

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential treating diseases such as cancer and infectious, inflammatory, neurodegenerative diseases, especially those with "undruggable" pathogenic targets. With recent rise of "molecular glue" type degraders, which tighten simplify connection an E3 ligase ubiquitination subsequent degradation, new therapies unmet medical needs are being designed developed. Here we use data from CAS Content Collection publication landscape research on targeted degraders provide insights into these molecules, special focus molecular glues. We also outline advantages glues summarize advances in practices glue degraders. further thorough review candidates through recruitment. Finally, highlight progression pipelines their diseases. Overall, our paper provides comprehensive reference support future development medicine.

Language: Английский

Citations

112
Cancer treatments: Past, present, and future DOI
Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher

et al.

Cancer Genetics, Journal Year: 2024, Volume and Issue: 286-287, P. 18 - 24

Published: June 17, 2024

Language: Английский

Citations

111
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2 DOI Creative Commons
Xingui Liu, Alexia F. Kalogeropulou, Sofia Domingos

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(37), P. 16930 - 16952

Published: Aug. 25, 2022

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 inhibitors, which, however, limitations as inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report development LRRK2 proteolysis targeting chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based ligands E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), cellular inhibitor apoptosis (cIAP) identified best degraders containing thioether-conjugated VHL ligand VH101. A second round medicinal chemistry exploration led qualifying XL01126 a fast potent multiple cell lines, DC50 values within 15–72 nM, Dmax ranging from 82 90%, degradation half-lives spanning 0.6 2.4 h. exhibits high permeability forms positively cooperative ternary complex (α = 5.7), compensates substantial loss binary binding affinities LRRK2, underscoring its strong performance cells. Remarkably, orally bioavailable (F 15%) penetrate blood–brain barrier after either oral or parenteral dosing mice. Taken together, these experiments qualify suitable probe study noncatalytic scaffolding functions vitro vivo offer attractive starting point future drug development.

Language: Английский

Citations

110
Rational Design in Photopharmacology with Molecular Photoswitches DOI Creative Commons
Piermichele Kobauri, Frank J. Dekker, Wiktor Szymański

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(30)

Published: April 7, 2023

Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into structure biologically active small molecules to allow optical control their potency. Going beyond trial and error, photopharmacology has progressively applied rational design methodologies devise light-controlled bioactive ligands. this review, we categorize photopharmacological efforts from standpoint medicinal chemistry strategies, focusing on diffusible photochromic ligands modified that operate through E-Z bond isomerization. vast majority cases, photoswitchable designed as analogs existing compounds, a variety approaches. By analyzing in detail comprehensive list instructive examples, describe state art discuss future opportunities photopharmacology.

Language: Английский

Citations

106
Chasing molecular glue degraders: screening approaches DOI
Ana Domostegui, Luis Nieto‐Barrado, Carles Perez‐Lopez

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(13), P. 5498 - 5517

Published: Jan. 1, 2022

By orchestrating interactions to an E3 ubiquitin ligase, molecular glue degraders have incredible therapeutic potential against otherwise “undruggable” proteins. We discuss how their discovery is evolving from serendipity intentional strategies.

Language: Английский

Citations

105
PROTAC-DB 2.0: an updated database of PROTACs DOI Creative Commons
Gaoqi Weng,

Xuanyan Cai,

Dongsheng Cao

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1367 - D1372

Published: Oct. 27, 2022

Proteolysis targeting chimeras (PROTACs), which harness the ubiquitin-proteasome system to selectively induce targeted protein degradation, represent an emerging therapeutic technology with potential modulate traditional undruggable targets. Over past few years, this has moved from academia industry and more than 10 PROTACs have been advanced into clinical trials. However, designing potent desirable drug-like properties still remains a great challenge. Here, we report updated online database, PROTAC-DB 2.0, is repository of structural experimental data about PROTACs. In 2nd release, expanded number 3270, corresponds 96% expansion over first version. Meanwhile, numbers warheads (small molecules proteins interest), linkers, E3 ligands recruiting ligases) increased 360, 1500 80, respectively. addition, given importance limited crystal target-PROTAC-E3 ternary complex structures, provide predicted structures for good degradation capability using our PROTAC-Model method. To further facilitate analysis PROTAC data, new filtering strategy based on ligases also added. 2.0 available at http://cadd.zju.edu.cn/protacdb/.

Language: Английский

Citations

103