Palbociclib as an Antitumor Drug: A License to Kill DOI Creative Commons
Agnieszka Łupicka‐Słowik, Federica Cossu, Marcin Sieńczyk

и другие.

Molecules, Год журнала: 2024, Номер 29(22), С. 5334 - 5334

Опубликована: Ноя. 13, 2024

Neoplastic cells are characterized by uncontrolled cell divisions caused cycle dysregulation. Key regulatory proteins governing the transition from G1 to S phase CDK4 and CDK6 kinases, which controlled D-type cyclins. The CDK4/6 kinases enable use of these as targets for anticancer therapy because they prevent growth development malignant inhibiting their activity. This paper surveys clinical trial results concerning palbociclib, first in-class FDA-approved drug hormone-dependent breast cancer. It discusses therapeutic applications in cancer well solid tumors hematopoietic malignancies. Additionally, presents an analysis palbociclib resistance acquired during explores new approaches, such modifications that enhance its desired activity or open up possibilities (PROTACs).

Язык: Английский

Advancing target validation with PROTAC technology DOI
Margaret Spitz,

Aseel Kashkush,

Raphael I. Benhamou

и другие.

Expert Opinion on Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Апрель 5, 2025

Targeted protein degradation (TPD) is a cutting-edge technology that provides new avenues for drug discovery and development. PROteolysis TArgeting Chimeras (PROTACs) are the most established advanced TPD strategy, enabling selective of disease-associated 'undruggable' proteins interest (POIs) by leveraging cell's natural machinery. To confirm PROTAC-induced proximity drives degradation, target validation ternary complex formation must be thoroughly assessed. In this perspective, authors detail some widely used in silico, structural, vitro, cellulo methods to validate PROTAC engagement formation. Additionally, they discuss growing use PROTACs as chemical probes novel identification validation. Target essential approach, ongoing studies should prioritize confirming using assays conducted under physiologically relevant cellular conditions. The believe proteomics analyses among valuable tools elucidating mechanism, selectivity, outcomes PROTACs. They also remain optimistic about future development their engagement. While rapidly advancing, it still holds vast opportunities exploration, offering significant potential further both biological research drive drugs.

Язык: Английский

Процитировано

0

Optimization of the PROTAC linker region of the proteasome substrate receptor hRpn13 rationalized structural modeling with molecular dynamics DOI Creative Commons
Xiuxiu Lu, Venkata R. Sabbasani, Bakar A. Hassan

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108520 - 108520

Опубликована: Апрель 1, 2025

Proteasome substrate receptor hRpn13 is a promising target for cancer therapy. PROTACs induce apoptosis by targeting the proteolytic product hRpn13Pru, which contains an intact ubiquitin- and proteasome-binding Pru domain. We generated PROTAC series based on hRpn13Pru-targeting XL5 varying linker that connects it to warhead against VHL-based ubiquitin E3 ligase machinery. Among eight tested derivatives, XL5-VHL-7 with -(CH2)5- alkyl promoted hRpn13Pru degradation induced cellular 2-fold improved potency compared original PROTAC. By using this slight chemical modifications in region, we were able evaluate efficacy of structural modeling molecular dynamics refining PROTACs. Overall, found experimental data correlated predictions modeling. Moreover, could observe hRpn13:PROTAC:VHL complexes 2D NMR support stronger affinity Our further indicate higher within VHL complex present than alone. Altogether, develop increased optimizing demonstrate current benefit limitations including aid optimization.

Язык: Английский

Процитировано

0

Targeted protein degradation for cancer therapy DOI
Matthias Hinterndorfer, Valentina A. Spiteri, Alessio Ciulli

и другие.

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Апрель 25, 2025

Язык: Английский

Процитировано

0

Recent advances in degraders engaging lysosomal pathways and related nanomedicine DOI

Runxin Lu,

Xiaofeng Ni, Sha Diao

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117701 - 117701

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα) DOI
Rohan Kalyan Rej, Biao Hu, Zhixiang Chen

и другие.

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

Опубликована: Ноя. 25, 2024

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment ER-positive (ER+) breast cancers, but new strategies are urgently needed to overcome clinical resistance. In present study, we describe discovery and extensive evaluation ERD-12310A as exceptionally potent orally efficacious PROTAC degrader ERα. achieved a DC

Язык: Английский

Процитировано

3

Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer DOI
Ranjan Kumar Acharyya, Rohan Kalyan Rej, Biao Hu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(21), С. 19010 - 19037

Опубликована: Ноя. 1, 2024

Despite the development of highly effective therapies for treatment estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current requires novel therapeutic strategies. Herein, we report discovery ERD-1233 as a potent and orally efficacious ERα degrader designed using PROTAC technology. was developed based on Lasofoxifene ER binding moiety cereblon ligand through extensive optimization linker. potently effectively reduces protein in vitro achieves excellent oral bioavailability mice rats. Oral administration ER+ tumors tumor regression wild-type MCF-7 xenograft model strong growth inhibition ESR1Y537S mutated mice. Our data demonstrate that is promising evaluation new therapy cancer.

Язык: Английский

Процитировано

2

Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond DOI Creative Commons
Carl Alexander Sandhof, Helen C. Murray,

M. Catarina Silva

и другие.

Neurotherapeutics, Год журнала: 2024, Номер unknown, С. e00499 - e00499

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

2

Current Therapeutic Opportunities for Estrogen Receptor Mutant Breast Cancer DOI Creative Commons
Murugesan Palaniappan

Biomedicines, Год журнала: 2024, Номер 12(12), С. 2700 - 2700

Опубликована: Ноя. 26, 2024

Estrogen receptor α (ERα) drives two out of three breast cancers and therefore ERα is a major therapeutic target for ER-positive cancer patients. Drugs that inhibit activity or block estrogen synthesis in the body are currently being used clinic to treat have been quite successful controlling progression majority However, often becomes resistant these endocrine therapies, leading endocrine-resistant metastatic cancer, very aggressive leads death. Recent large-scale genomic studies revealed series activating somatic mutations gene (ESR1) Of these, Y537S D538G found at much higher rate patients with cancer. Remarkably, produce an transcriptional than wild type absence estradiol, traditional therapy has poor efficacy against ER mutants. Therefore, development new drugs mutants unmet clinical need This review summarizes recent preclinical trials targeting mutant

Язык: Английский

Процитировано

1

Palbociclib as an Antitumor Drug: A License to Kill DOI Creative Commons
Agnieszka Łupicka‐Słowik, Federica Cossu, Marcin Sieńczyk

и другие.

Molecules, Год журнала: 2024, Номер 29(22), С. 5334 - 5334

Опубликована: Ноя. 13, 2024

Neoplastic cells are characterized by uncontrolled cell divisions caused cycle dysregulation. Key regulatory proteins governing the transition from G1 to S phase CDK4 and CDK6 kinases, which controlled D-type cyclins. The CDK4/6 kinases enable use of these as targets for anticancer therapy because they prevent growth development malignant inhibiting their activity. This paper surveys clinical trial results concerning palbociclib, first in-class FDA-approved drug hormone-dependent breast cancer. It discusses therapeutic applications in cancer well solid tumors hematopoietic malignancies. Additionally, presents an analysis palbociclib resistance acquired during explores new approaches, such modifications that enhance its desired activity or open up possibilities (PROTACs).

Язык: Английский

Процитировано

0