Novel Indazole Compounds as PKMYT1 Kinase Inhibitors for Treating Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(11), P. 1810 - 1811

Published: Oct. 12, 2024

Provided herein are novel indazole compounds as PKMYT1 kinase inhibitors, pharmaceutical compositions, use of such in treating cancer, and processes for preparing compounds.

Language: Английский

Novel 1,6-Naphthridine Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(3), P. 371 - 372

Published: Feb. 14, 2025

Provided herein are novel 1,6-naphthridine compounds as SMARCA2 inhibitors, pharmaceutical compositions, use of such in treating non-small cell lung cancer and processes for preparing compounds.

Language: Английский

Citations

1
Compromised epigenetic robustness in cancer: fueling evolution, exposing weakness DOI Creative Commons
Thomas Stuart Wilson, Paola Scaffidi

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The complex network of proteins that regulate chromatin and DNA methylation landscapes is often disrupted in cancer. Clonal subclonal mutations targeting a wide range molecular functions are frequently observed across cancer types, emerging evidence suggests loss robust epigenetic control promotes both initiation evolution, independently context-specific effects. Here, we review how diverse genetic alterations destabilize the regulatory (ERN) may converge into common phenotypes. We also discuss implications altered topology systemic disorder for vulnerability, therapeutic resistance cancers.

Language: Английский

Citations

1
Discovery of 1-phenyl-1,2,3-triazole ureas as dual VEGFR-2/JNK-1 type II kinase inhibitors targeting pancreatic cancer DOI
Wagdy M. Eldehna, Eslam Roshdy,

Maha-Hamadien Abdulla

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142372 - 142372

Published: March 1, 2025

Language: Английский

Citations

1
Targeting the DNA damage response in cancer DOI Creative Commons

Guffanti Federica,

Chiappa Michela,

Giovanna Damia

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(11)

Published: Oct. 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.

Language: Английский

Citations

5
Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models DOI

Sai Yang,

Xiaowen Gu,

Lei Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit homozygous deletion S-methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report identification novel inhibitors featuring spiral ring to circumvent C-N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency enzymatic activity (IC50 = 7 nM) and HCT-116 MTAP(-/-) cell 17 nM). Further optimization has led two new lead compounds: brain-penetrant compound, 29-1, potent but limited 39. Both these compounds demonstrate increased plasma exposure significant efficacy xenograft models are depleted MTAP. We hope identifying inhibitor will create opportunities explore potential therapeutic effects S-adenosylmethionine modulation central nervous system.

Language: Английский

Citations

0
Research Progress in DNA Damage Response (DDR)-Targeting Modulators: from Hits to Clinical Candidates DOI
Binbin Cheng, Zongbao Ding,

Yun Hong

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117347 - 117347

Published: Feb. 1, 2025

Language: Английский

Citations

0
The evolving landscape of genetic biomarkers for immunotherapy in primary and metastatic breast cancer DOI Creative Commons
Liang Jin, Zijian Yang, Wei Tang

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 13, 2025

Background Major advances have been achieved in the characterization of primary breast cancer genomic profiles. Limited information is available on profile tumors originating from different metastatic locations recurrent/metastatic (R/M) cancer, especially Asian patients. This study aims to decipher mutational profiles and R/M Chinese patients using next-generation sequencing. Methods A total 563 were enrolled, 590 tumor tissues matched peripheral blood samples collected subjected targeted sequencing with a panel 1,021 cancer-related genes. The mutation spectrum, DNA damage response (DDR) genes, commonly altered signal pathways, immunotherapy-related markers compared between cancer. molecular differences our cohort Memorial Sloan Kettering Cancer Center (MSKCC) dataset also explored. Results 361 229 analyzed. BRCA2, ATRX , ATM more frequently observed lesions among 36 DDR An ESR1 PD-L1 PD-L2 amplification enriched (all p <0.05). Compared MSKCC dataset, we recruited diagnosed at age 50 or younger triple-negative (TNBC) subtypes. TNBC had higher percentage metastasis ( Conclusions revealed distinctive features patients, which are those Western countries. enrichment indicates necessity re-biopsy for immunotherapy.

Language: Английский

Citations

0
Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity DOI Creative Commons
Mirco Masi, Laura Poppi, Viola Previtali

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 16, 2025

Abstract The RAD51-BRCA2 interaction is central to DNA repair through homologous recombination. Emerging evidence indicates RAD51 overexpression and its correlation with chemoresistance in various cancers, suggesting inhibition as a compelling avenue for intervention. We previously showed that combining olaparib (a PARP inhibitor (PARPi)) RS -35d BRCA2-RAD51 inhibitor) was efficient killing pancreatic ductal adenocarcinoma (PDAC) cells. However, impaired cell viability even when administered alone, potential off-target effects. Here, multiple, integrated orthogonal biological approaches different 2D 3D PDAC cultures, we characterised enantiomers, terms of mode action single contributions. By differentially inhibiting both sensor kinases ATM, ATR DNA-PK, enantiomers exhibit ‘within-pathway synthetic lethality’ profile. To the best our knowledge, this first reported proof-of-concept small molecule capable demonstrating built-in synergism. In addition, effect on BRCA2 -mutated, olaparib-resistant cells suggests compound may be effective an anticancer agent possibly overcoming PARPi resistance. Our results demonstrate lethality, diversified applications, propose new concrete opportunities effectively kill cancer while limiting side effects potentially emerging drug

Language: Английский

Citations

0
Role of PARP Inhibitors: A New Hope for Breast Cancer Therapy DOI Open Access

K De,

Malabendu Jana,

Bhabadeb Chowdhury

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2773 - 2773

Published: March 19, 2025

Tumors formed by the unchecked growth of breast cells are known as cancer. The second most frequent cancer in world is It common among females. In 2022, 2,296,840 women were diagnosed with therapy evolving through development Poly (ADP-ribose) polymerase (PARP) inhibitors, which offering people specific genetic profiles new hope research into disease continues. focuses on patients BRCA1 and BRCA2 mutations. This review summarizes recent mechanisms action PARP inhibitors their implications for therapy. We how therapeutic applications developing highlight studies showing effectiveness these medicines whether used alone or combination. Furthermore, significance customized highlighted enhancing patient outcomes we address function testing identifying candidates inhibition. Recommendations future areas to maximize potential also included, along challenges limits clinical usage. objective this improve our comprehension complex interaction between biology knowledge will help guide screening approaches, practice, support preventive initiatives at risk.

Language: Английский

Citations

0
1,6-Naphthridine Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Provided herein are novel 1,6-naphthridine compounds as SMARCA2 inhibitors, pharmaceutical compositions, use of such in treating non-small cell lung cancer and processes for preparing compounds.

Language: Английский

Citations

0