CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

Nature, Journal Year: 2022, Volume and Issue: 604(7907), P. 749 - 756

Published: April 20, 2022

Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling resistance to cytotoxic targeted therapies

Language: Английский

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A new wave of innovations within the DNA damage response

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 8, 2023

Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance genome integrity cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting processes could induce excessive damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit patients with breast (BRCA) mutation homologous recombination deficiency (HRD), which proves concept synthetic lethality treatment. Moreover, other two scenarios inhibitor application, replication stress and combination chemo- radio- therapy, are under active clinical exploration. In this review, we revisited progress therapy beyond launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, maintain efficacy while mitigating side effects, may diversify application clinic. Albeit unavoidable on-mechanism toxicities, several small molecules checkpoints (gatekeepers) shown great promise preliminary results, warrant further evaluations. addition, repair pathways (caretakers) also preclinical development. With these progresses efforts, envision a new wave innovations within come age.

Language: Английский

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

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11488 - 11521

Published: July 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.

Language: Английский

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The Science and Art of Structure-Based Virtual Screening

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(4), P. 436 - 440

Published: March 25, 2024

Structure-based virtual screening has gained momentum again as the high attrition rate at every stage of drug discovery drives need to explore a greater chemical space. From Bayesian perspective, its shortcomings viable strategy for sustainable hit are discussed, with regard prior rates libraries and performance computational methods. Lessons shared in selecting hits experimental validation learned from series eight successful campaigns, one which impacted candidate currently clinical trials.

Language: Английский

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Myt1 kinase inhibitors - Insight into structural features, offering potential frameworks

Chemico-Biological Interactions, Journal Year: 2024, Volume and Issue: 391, P. 110901 - 110901

Published: Feb. 6, 2024

Language: Английский

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Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma

EMBO Molecular Medicine, Journal Year: 2024, Volume and Issue: 16(5), P. 1115 - 1142

Published: April 3, 2024

Language: Английский

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Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(3)

Published: June 9, 2023

Abstract Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control genome maintenance. This creates specific vulnerabilities may be exploited therapeutically. WEE1 kinase a key kinase, it has emerged as promising therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong interaction between PKMYT1 led us to hypothesize multiple low-dose approach utilizing joint inhibition would allow exploitation of the synthetic lethality. We found exhibited synergistic eradicating ovarian cells organoid models at low dose. The synergistically promoted CDK activation. Furthermore, combined treatment exacerbated catastrophe, leading increase genomic instability inflammatory STAT1 signalling These findings suggest new harness potency lethal contribute development treatments for cancer.

Language: Английский

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PKMYT1 Is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer

Molecular Cancer Therapeutics, Journal Year: 2024, Volume and Issue: 23(10), P. 1494 - 1510

Published: May 23, 2024

Abstract Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients 22 ER+ cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth E2-independent. clinical samples, high PKMYT1 mRNA levels associated to both ET CDK4/6 inhibition. The inhibitor lunresertib (RP-6306) gemcitabine selectively synergistically reduced viability palbociclib-resistant cells without functional p53. vitro combination increased DNA damage apoptosis. palbociclib-resistant, TP53 mutant PDX-derived organoids PDXs, RP-6306 low-dose induced greater tumor volume reduction compared either single agent. Our study demonstrates potential resistant cancer.

Language: Английский

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Patent highlights June — July 2024

Pharmaceutical Patent Analyst, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 5

Published: March 7, 2025

A snapshot of noteworthy recent developments in the patent literature relevance to pharmaceutical and medical research development.

Language: Английский

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Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 1, 2025

Abstract Ovarian cancers (OVCAs) and endometrial (EMCAs) with CCNE1- amplification are often resistant to standard treatment represent an unmet clinical need. Synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal CCNE1 -amplification. We hypothesize that -amplification associated replication stress will be more effectively targeted by combining PKMYT1 inhibitor lunresertib (RP-6306), ATR camonsertib (RP-3500/RG6526). Low dose combination RP-6306 RP-3500 synergistically increases cytotoxicity so in -amplified compared non-amplified cells. Combination produces durable antitumor activity, reduces metastasis survival patient-derived OVCA EMCA xenografts. Mechanistically, low doses increase activation than monotherapy, triggering rapid robust induction premature mitosis, DNA damage, apoptosis a -dependent manner. These findings suggest targeting activity is effective therapeutic approach treat -amplifed OVCAs EMCAs.

Language: Английский

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