New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(14), С. 11488 - 11521

Опубликована: Июль 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Язык: Английский

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Targeting the DNA damage response in cancer

MedComm, Год журнала: 2024, Номер 5(11)

Опубликована: Окт. 31, 2024

DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.

Язык: Английский

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Research Progress in DNA Damage Response (DDR)-Targeting Modulators: from Hits to Clinical Candidates

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 287, С. 117347 - 117347

Опубликована: Фев. 1, 2025

Язык: Английский

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Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. inhibition induces accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment cancers with defects. Herein, we describe discovery preclinical evaluation YY2201, highly potent selective novel inhibitor, favorable ADME, safety pharmacology, pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression broad-spectrum types, both vitro vivo. shows superior vivo anticancer efficacy better therapeutic index compared AZD6738 lung xenograft model. also exhibits suppression effects combination chemotherapy Currently, investigational new drug application has been approved by FDA further clinical investigation.

Язык: Английский

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Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2025, Номер 40(1)

Опубликована: Апрель 21, 2025

This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related (ATR), DNA-dependent protein kinase (DNA-PK) in DNA damage response (DDR) their implications cancer. Emphasis is placed on intricate interplay between these kinases, highlighting collaborative distinct maintaining genomic integrity promoting tumour development under dysregulated conditions. Furthermore, covers ongoing clinical trials, patent literature, medicinal chemistry campaigns ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, employed robust drug design strategies aimed at assembling new structural templates with amplified DDR inhibitory ability, well outwitting pharmacokinetic liabilities existing inhibitors. Given success attained through such endeavours, pipeline repair anticipated to be supplemented by a reasonable number tractable entries (DDR inhibitors) soon.

Язык: Английский

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Identification and Biosynthesis of anN-Glucuronide Metabolite of Camonsertib

Drug Metabolism and Disposition, Год журнала: 2024, Номер 52(5), С. 368 - 376

Опубликована: Фев. 20, 2024

Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an N-glucuronide metabolite camonsertib. was first observed human hepatocyte incubations subsequently isolated to determine structure, evaluate its stability as part bioanalytical method use standard estimating concentration phase I samples. The scaled-up using purified bacterial culture preparation preparative chromatography. generated sufficient material glucuronide allow one- two-dimensional ¹H ¹³C NMR structural elucidation further characterization. nuclear Overhauser effect data combined with gradient heteronuclear multiple bond correlation experiment molecular modeling, strongly suggests that point attachment results formation (2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(5-(4-((1R,3r,5S)-3-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)-6-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-2-carboxylic acid.

SIGNIFICANCE STATEMENT

report camonsertib formed by incubations. study reveals structure detailed after scale-up approach yielding significant quantities metabolite.

Язык: Английский

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Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(15), С. 12735 - 12759

Опубликована: Июль 25, 2024

The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it promising target for antitumor drug development through synthetic lethality. In this study, we present discovery detailed characterization of AD1058, highly potent selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy inhibiting cell proliferation, disrupting cycle, inducing apoptosis compared to AZD6738. displays effects as single agent or combination clinically approved tumor therapies such PARP inhibitors, ionizing radiotherapy, chemotherapy vivo. Considering its enhanced ability permeate blood–brain barrier, is clinical candidate treatment brain metastases leptomeningeal solid tumors. Additionally, among reported features shortest synthesis route highest efficiency date.

Язык: Английский

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Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 4, 2024

One of the hallmarks cancer is high levels DNA replication stress and defects in damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia Rad3-related protein (ATR) a key regulator DDR machinery an attractive therapeutic target, with multiple ATR inhibitors holding significant promise ongoing clinical studies. Herein, we describe discovery characterization ART0380 (6), potent selective inhibitor compelling vitro vivo pharmacological profile currently undergoing Phase 2 studies patients advanced or metastatic solid tumors as monotherapy combination DNA-damaging agents (NCT04657068 NCT05798611). (6) has favorable human PK suitable both intermittent continuous once-daily (QD) dosing, characterized by dose-proportional increase exposure low variability.

Язык: Английский

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