Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(2), P. 420 - 444

Published: July 23, 2018

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or metabolic syndrome. Polypharmacological profiles can produce additive synergistic effects while reducing side and significantly contribute high therapeutic success indispensable drugs aspirin. While their identification has long been result serendipity, medicinal chemistry now tends design polypharmacology. Modern vitro pharmacological methods chemical probes allow systematic search for rational combinations recent innovations computational technologies, crystallography, fragment-based equip multitarget compound development with valuable tools. In this Perspective, we analyze multiple ligands versatile toolbox We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential secure future innovation.

Language: Английский

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Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 62(20), P. 8881 - 8914

Published: May 13, 2019

Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation multiple targets may improve both therapeutic safety and efficacy, compared with drugs. However, few multitarget are on market or in clinical trials, despite best efforts medicinal chemists. This article discusses systematic establishment target combination, lead generation, optimization multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases recent years physicochemical properties 117 drugs, aim reveal trends insights potential use MTDLs.

Language: Английский

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Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Molecules, Journal Year: 2021, Volume and Issue: 26(9), P. 2601 - 2601

Published: April 29, 2021

Despite enormous progress in the treatment of many malignancies, development cancer resistance is still an important reason for chemotherapy failure. Increasing knowledge cancers’ molecular complexity and mechanisms their to anticancer drugs, as well extensive clinical experience, indicate that effective fight against requires a multidimensional approach. Multi-target may be achieved using drugs combination, co-delivery medicines, or designing hybrid drugs. Hybrid simultaneously targeting points signaling networks various structures within cell have been extensively explored recent years. The single agent can modulate multiple targets involved proliferation, possesses simpler pharmacokinetic profile reduce possibility drug interactions occurrence, facilitates process development. Moreover, medication expected enhance patient compliance due less complicated regimen, diminished number adverse reactions toxicity comparison combination As consequence, efforts made design molecules different chemical functions means circumvent resistance. studies this field encouraged us review available literature present selected research results highlighting possible role overcoming

Language: Английский

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Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(2), P. 922 - 951

Published: Jan. 12, 2024

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance the expression of normal networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some which entered clinical trials, including eight irreversible (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, LH-1802) reversible (CC-90011 SP-2577). Most demonstrated enhanced efficacy combination with other agents. multitarget also exampled by dual LSD1/histone deacetylases (HDACs) 4SC-202 JBI-802. Herein, we present comprehensive overview various antitumor agents, as well inhibitors. Additionally, challenges future research directionsare discussed, hope this review will provide new insight into development LSD1-targeted anticancer

Language: Английский

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Design, synthesis and biological evaluation of dual CDK9/PARP inhibitors for the treatment of cancer

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117367 - 117367

Published: Feb. 5, 2025

Language: Английский

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Overcoming cancer therapy resistance: From drug innovation to therapeutics

Drug Resistance Updates, Journal Year: 2025, Volume and Issue: 81, P. 101229 - 101229

Published: March 8, 2025

Language: Английский

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Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(7), P. 3171 - 3183

Published: Nov. 12, 2018

Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved cancer treatment, numerous others undergoing clinical trials. It has well validated that an agent can simultaneously effectively inhibit two or more may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment potentiating synergistic effects. A prime example of a bifunctional is the hybrid HDAC inhibitor. In this perspective, authors review majority reported kinase/HDAC inhibitors.

Language: Английский

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RGD Peptide‐Based Target Drug Delivery of Doxorubicin Nanomedicine

Drug Development Research, Journal Year: 2017, Volume and Issue: 78(6), P. 283 - 291

Published: Aug. 16, 2017

ABSTRACT Preclinical Research Doxorubicin (DOX) is commonly used for the treatment of breast cancer and lymphoma. However, its clinical use has been severely limited due to cardiotoxicity, requiring development safer more efficient pharmaceutical formulations DOX. Advances in nanotechnology have provided new ways administer chemotherapeutic drugs like DOX are conveyed into body tumor sites. These Nanotechnology approaches aided selective accumulation sites via enhanced permeability retention. absence active targeting ligands still hinders effective delivery Among all developed date, RGD peptide (Arginylglycylaspartic acid) occupies a unique position owing inherent safety, biocompatibility, ability. Accordingly, modification with ligand anticipated improve transport cells. In this review, we discuss using improving therapeutic efficacy nanomedicine. Drug Dev Res 78 : 283–291, 2017. © 2017 Wiley Periodicals, Inc.

Language: Английский

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Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(15), P. 10581 - 10605

Published: July 27, 2021

The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the strategy incorporating second activity into existing single-active ligand. If binding sites both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with functional groups. are large or adjacent to solution, key pharmacophores fused directly. regions small deep inside proteins, linked-pharmacophore might only way. added should not affect mode original ones. Moreover, inhibitory activities need adjusted achieve optimal ratio.

Language: Английский

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Cancer drug development: The missing links

Experimental Biology and Medicine, Journal Year: 2019, Volume and Issue: 244(8), P. 663 - 689

Published: April 8, 2019

Although better science and technology has been linked with health care, however, reality is much different. America most of Europe are equipped advanced technology, paradoxically cancer incidence highest in the world. This indicates that alone not sufficient treating diseases like cancer. It also now well recognized more than 95% drugs/compounds kill either cells culture or regress tumors animals, fail phase I clinical trials humans, indicating pre-clinical models inadequate. In addition, anticancer drugs approved by regulatory agencies such as FDA no effect on overall survival patient may provide an increase few months survival. despite fact targeted therapies currently available highly expensive; thus suggesting lack affordability. review meant to focus some these problems detail then potential solutions since cancers caused multiple genes, multi-targeted needed natural products which inexpensive, safe have used for thousands years both prevention treatment Impact statement The success rate enter into 1 utterly less. Why vast majority understood but suggests studies adequate human diseases. 1975, per Tufts Center Study Drug Development, pharmaceutical industries expended 100 million dollars research development average drug. By 2005, this figure had quadrupled, $1.3 billion. order recover their high risky investment cost, companies charge products. However, there exists correlation between drug cost actual sale could be due reason all patients might respond Hence, a given tested large number show benefits obtain significant results.

Language: Английский

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