Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy

Campiani, Giuseppe; Khan, Tuhina; Ulivieri, Cristina; Staiano, Leopoldo; Papulino, Chiara; Magnano, Stefania; Nathwani, Seema M.; Ramunno, Anna; Lucena‐Agell, Daniel; Relitti, Nicola; Federico, Stefano; Pozzetti, Luca; Carullo, Gabriele; Casagni, Alice; Brogi, Simone; Vanni, Francesca; Galatello, Paola; Ghanim, Magda; McCabe, Niamh; Lamponi, Stefania; Valoti, Massimo; Ibrahim, Ola; O'Sullivan, Jeff; Turkington, Richard; Kelly, Vincent P.; VanWemmel, Ruben; Díaz, J. Fernando; Gemma, Sandra; Zisterer, Daniela M.; Altucci, Lucia; Matteis, Antonella De; Butini, Stefania; Altucci, Lucia

doi:10.1016/j.ejmech.2022.114274

Cited by 6 publications

(5 citation statements)

References 80 publications

(93 reference statements)

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“…Microtubule-targeting agents (MTAs) have been widely used as antitumor chemotherapeutic agents [23][24][25]. They play essential roles in the dynamics and structure of the microtubule, such as disturbing mitotic spindle formation, and interrupting the cell cycle progression in the metaphase/anaphase of mitosis [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New Biaryl Derivatives of Cycloalkyl diacetamide Bearing Chalcone Moiety as type II c-MET Kinase Inhibitors

Salarinejad

Seyfi

Hayashi

et al. 2023

Preprint

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Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 25 nM and 46 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New Biaryl Derivatives of Cycloalkyl diacetamide Bearing Chalcone Moiety as type II c-MET Kinase Inhibitors

Salarinejad

Seyfi

Hayashi

et al. 2023

Preprint

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“…MTAs disrupt the dynamic instability of microtubules, prevent mitotic spindle formation, arrest the cell cycle and induce cell apoptosis . Efforts to discover new MTAs for chemotherapy are ongoing. − Presently, certain MTAs, including taxanes (paclitaxel, docetaxel, and cabazitaxel), − vinca alkaloids (vinblastine, vincristine, and vinorelbine), ,, ixabepilone, and eribulin mesylate, have been approved by US Food and Drug Administration to treat solid tumors and hematological malignancies. These chemotherapeutic drugs are frequently combined with other targeting drugs or integrated in curative regimens .…”

Section: Introductionmentioning

confidence: 99%

Recent Progress on Microtubule Degradation Agents

Zhang,

Zhao,

Wang

et al. 2023

J. Med. Chem.

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Targeted protein degradation (TPD) has emerged as the most promising approach for the specific knockdown of disease-associated proteins and is achieved by exploiting the cellular quality control machinery. TPD technologies are highly advantageous in overcoming drug resistance as they degrade the whole target protein. Microtubules play important roles in many cellular processes and are among the oldest and most well-established targets for tumor chemotherapy. However, the development of drug resistance, risk of hypersensitivity reactions, and intolerable toxicities severely restrict the clinical applications of microtubuletargeting agents (MTAs). Microtubule degradation agents (MDgAs) operate via completely different mechanisms compared with traditional MTAs and are capable of overcoming drug resistance. The emergence of MDgAs has expanded the scope of TPD and provided new avenues for the discovery of tubulin-targeted drugs. Herein, we summarized the development of MDgAs, and discussed their degradation mechanisms, mechanisms of action on the binding sites, potential opportunities, and challenges. ■ SIGNIFICANCE (1) MDgAs exhibited completely different mechanisms compared with traditional MTAs. (2) MDgAs can overcome MDR by promoting tubulin proteasome-dependent degradation. (3) MDgAs have expanded the scope of TPD and provided a new perspective for tubulin-targeted drug discovery.

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“…It is known that the causes of cancer, diabetes, inflammatory processes, and other multifactorial diseases are mutation processes and/or activation of enzymes of the protein kinase family [38,39]. The human genome contains 518 kinases that transfer the γ-phosphate of ATP to the hydroxyl group of tyrosine, serine, or threonine residues of the substrate.…”

Section: Introductionmentioning

confidence: 99%

“…Using the PASS Online software, among the previously synthesized and new hybrid and chimeric derivatives of 1,2-dithiolo [3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity, and experimentally confirmed their inhibitory activity. For the leading compounds It is known that the causes of cancer, diabetes, inflammatory processes, and other multifactorial diseases are mutation processes and/or activation of enzymes of the protein kinase family [38,39]. The human genome contains 518 kinases that transfer the γ-phosphate of ATP to the hydroxyl group of tyrosine, serine, or threonine residues of the substrate.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors

Медведева

Shikhaliev

2022

Molecules

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This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC50 values. It was revealed that compounds 2a, 2b, 2c, and 2q displayed a significant inhibition JAK3 (IC50 = 0.36 μM, 0.38 μM, 0.41 μM, and 0.46 μM, respectively); moreover, compounds 2a and 2b displayed excellent activities against NPM1-ALK (IC50 = 0.54 μM, 0.25 μM, respectively), against cRAF[Y340D][Y341D], compound 2c showed excellent activity, and compound 2q showed weak activity (IC50 = 0.78 μM, 5.34 μM, respectively) (sorafenib IC50 = 0.78 μM, 0.43 μM, 1.95 μM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.

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Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy

Cited by 6 publications

References 80 publications

Design, Synthesis, and Biological Evaluation of New Biaryl Derivatives of Cycloalkyl diacetamide Bearing Chalcone Moiety as type II c-MET Kinase Inhibitors

Design, Synthesis, and Biological Evaluation of New Biaryl Derivatives of Cycloalkyl diacetamide Bearing Chalcone Moiety as type II c-MET Kinase Inhibitors

Recent Progress on Microtubule Degradation Agents

Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors

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