Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As
Potent Multiaction Agents Inducing Antiproliferative Effects in
2D and 3D Cancer Cell Models

J 2025

Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models

SHARKAWY, Sofia; Sourav ACHARYA; Hana KOSTRHUNOVA; Moumita MAJI; Lenka MARKOVA et al.

Základní údaje

Originální název

Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models

Autoři

SHARKAWY, Sofia; Sourav ACHARYA; Hana KOSTRHUNOVA; Moumita MAJI; Lenka MARKOVA; Vojtech NOVOHRADSKY; Dan GIBSON a Viktor BRABEC

Vydání

JOURNAL OF MEDICINAL CHEMISTRY, WASHINGTON, AMER CHEMICAL SOC, 2025, 0022-2623

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30104 Pharmacology and pharmacy

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.800 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/25:00143369

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

Antineoplastic agents; Cancer; Cells; Pharmaceuticals; Screening assays

Štítky

14313050, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 1. 2026 13:29, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

Novel Pt(IV) complexes conjugated with the kinase inhibitors crizotinib or ceritinib were synthesized and assessed for anticancer activity. Cisplatin-derived derivatives bearing phenylbutyrate and either crizotinib (complex 3) or ceritinib (complex 7) exhibited the greatest efficacy and selectivity against cancer cells while sparing noncancerous counterparts. Both compounds maintained activity in three-dimensional spheroid models, where they reduced viability, inhibited migration, and suppressed invasive outgrowth. Cellular accumulation studies confirmed efficient uptake of 3 and 7. Mechanistic investigations revealed that crizotinib-containing complexes induced G2/M arrest, whereas ceritinib analogs, particularly 7, caused S-phase arrest and DNA damage responses. Moreover, both agents triggered apoptosis and hallmarks of immunogenic cell death, including calreticulin exposure, ATP and HMGB1 release, and enhanced phagocytosis by macrophages. These findings highlight complexes 3 and 7 as promising multifunctional candidates that combine cytotoxic, anti-invasive, and immune-activating properties, supporting Pt(IV)–kinase inhibitor conjugates as a potential strategy for targeted cancer chemotherapy.

Citovat

SHARKAWY, Sofia; Sourav ACHARYA; Hana KOSTRHUNOVA; Moumita MAJI; Lenka MARKOVA; Vojtech NOVOHRADSKY; Dan GIBSON a Viktor BRABEC. Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models. JOURNAL OF MEDICINAL CHEMISTRY. WASHINGTON: AMER CHEMICAL SOC, 2025, roč. 68, č. 22, s. 24094-24107. ISSN 0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.5c01858.

@article{2547625,
   author = {Sharkawy, Sofia and Acharya, Sourav and Kostrhunova, Hana and Maji, Moumita and Markova, Lenka and Novohradsky, Vojtech and Gibson, Dan and Brabec, Viktor},
   article_location = {WASHINGTON},
   article_number = {22},
   doi = {https://doi.org/10.1021/acs.jmedchem.5c01858},
   keywords = {Antineoplastic agents; Cancer; Cells; Pharmaceuticals; Screening assays},
   language = {eng},
   issn = {0022-2623},
   journal = {JOURNAL OF MEDICINAL CHEMISTRY},
   title = {Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models},
   url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01858},
   volume = {68},
   year = {2025}
}

TY  - JOUR
ID  - 2547625
AU  - Sharkawy, Sofia - Acharya, Sourav - Kostrhunova, Hana - Maji, Moumita - Markova, Lenka - Novohradsky, Vojtech - Gibson, Dan - Brabec, Viktor
PY  - 2025
TI  - Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models
JF  - JOURNAL OF MEDICINAL CHEMISTRY
VL  - 68
IS  - 22
SP  - 24094-24107
EP  - 24094-24107
PB  - AMER CHEMICAL SOC
SN  - 00222623
KW  - Antineoplastic agents
KW  - Cancer
KW  - Cells
KW  - Pharmaceuticals
KW  - Screening assays
UR  - https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01858
N2  - Novel Pt(IV) complexes conjugated with the kinase inhibitors crizotinib or ceritinib were synthesized and assessed for anticancer activity. Cisplatin-derived derivatives bearing phenylbutyrate and either crizotinib (complex 3) or ceritinib (complex 7) exhibited the greatest efficacy and selectivity against cancer cells while sparing noncancerous counterparts. Both compounds maintained activity in three-dimensional spheroid models, where they reduced viability, inhibited migration, and suppressed invasive outgrowth. Cellular accumulation studies confirmed efficient uptake of 3 and 7. Mechanistic investigations revealed that crizotinib-containing complexes induced G2/M arrest, whereas ceritinib analogs, particularly 7, caused S-phase arrest and DNA damage responses. Moreover, both agents triggered apoptosis and hallmarks of immunogenic cell death, including calreticulin exposure, ATP and HMGB1 release, and enhanced phagocytosis by macrophages. These findings highlight complexes 3 and 7 as promising multifunctional candidates that combine cytotoxic, anti-invasive, and immune-activating properties, supporting Pt(IV)–kinase inhibitor conjugates as a potential strategy for targeted cancer chemotherapy.
ER  -

SHARKAWY, Sofia; Sourav ACHARYA; Hana KOSTRHUNOVA; Moumita MAJI; Lenka MARKOVA; Vojtech NOVOHRADSKY; Dan GIBSON a Viktor BRABEC. Crizotinib- or Ceritinib-Conjugated Platinum(IV) Prodrugs As Potent Multiaction Agents Inducing Antiproliferative Effects in 2D and 3D Cancer Cell Models. \textit{JOURNAL OF MEDICINAL CHEMISTRY}. WASHINGTON: AMER CHEMICAL SOC, 2025, roč.~68, č.~22, s.~24094-24107. ISSN~0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.5c01858.

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