Chemotherapeutic Agents Targeting Intracellular Signaling Pathways

Year 2021, , 175 - 184, 01.05.2021

Sevgi Uğur Mutluay , Leyla Didem Kozacı

https://doi.org/10.19127/bshealthscience.825971

Abstract

In cancer treatment, conventional chemotherapeutics have been in clinical use since 1940s. Even though their efficacy has been established for many years, selectivity problem and serious side effects limit their use. Disadvantages of available therapies and need for novel anti-cancer drugs induced a shift in research towards that direction. Over the past 20 years, by shedding light on
molecular mechanisms of cancer, intracellular proteins, that might be targets for new drugs, have been defined. Of these targets, primary ones are; PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubiquitin-Proteasom and Hedgehog pathways. These pathways and their downstream effectors shown to play a role in many cancer types. Protein kinases, which are involved in intracellular signaling pathways and found to be related to those pathways, are the molecules that are most studied. Many inhibitor molecules and/or monoclonal antibodies spesific to tyrosine and serine/theronine kinases have been developed and brought into use. Several members of tyrosine kinase family, which consists of around 20 subclasses, have been shown to be related to cancer. In this regard, prominent receptor tyrosine kinases can be sorted as EGFR, PDGFR, VEGFR, FLT3 and ALK. Other protein kinases; Src, BTK, CDK and AMPK have been reported to mediate critical processes in cancer development. Beside those targets, potential molecular targets and chemotherapeutic agents to these targets have been defined. Many molecules, that were developed to inhibit NOTCH, JAK-STAT, Nuclear Factor Kappa B, Wnt/ ß-Catenin pathways, Insulin, FGF, HGF, GSK-3 receptors, Protein Kinase C, Aurora Kinase and Hsp90 activity, are in stage of clinical study.

Keywords

Cancer, Chemotherapy, Signaling pathways, Targeted therapy, Protein kinase inhibitors

Hücre İçi Sinyal Yolaklarını Hedefleyen Kemoterapötik Ajanlar

Abstract

Kanser tedavisinde, konvansiyonel kemoterapötikler 1940’lı yıllardan beri klinikte kullanılmaktadırlar. Etkililikleri uzun yıllardır kanıtlanmış olsa da seçicilik sorunu ve ciddi yan etkilere yol açmaları bu ajanların kullanımını kısıtlar. Mevcut tedavilerin dezavantajları ve yeni anti-kanser ilaçlarına olan ihtiyaç araştırmaların bu yöne kaymasına neden olmuştur. Son 20 yılda kanserin
moleküler mekanizmalarının da aydınlatılması ile yeni ilaçlar için hedef olabilecek proteinler tanımlanmıştır. Bu hedeflerden başlıcaları PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubikitin-Proteazom ve Hedgehog yolaklarıdır. Bu yolakların ve efektörlerinin birçok kanser tipinde rolü olduğu gösterilmiştir. Hücre içi sinyal mekanizmalarında görev alan ve bu yolaklarla ilişkili bulunan protein
kinazlar üzerlerinde en çok çalışma yapılan moleküllerdir. Tirozin ve serin/treonin kinazlara özgü birçok inhibitör molekül ve/veya monoklonal antikor geliştirilmiş ve kullanıma sunulmuştur. Yaklaşık 20 alt sınıftan oluşan reseptör tirozin kinazların (RTK) birçok üyesinin kanserle ilişkili olduğu gösterilmiştir. Bu bağlamda öne çıkan RTK’lar; EGFR, PDGFR, VEGFR, FLT3 ve ALK olarak sıralanabilir. Diğer protein kinazlardan Src, BTK, CDK ve AMPK’nın kanser gelişimi ile ilgili kritik süreçlere aracılık ettiği bildirilmiştir. Bu hedeflerin yanısıra potansiyel moleküler hedefler ve bu hedeflere yönelik kemoterapötik ajanlar da belirlenmiştir. NOTCH, JAK-STAT, Nükleer Faktör Kappa B, Wnt/ ß-Catenin yolaklarını, İnsülin, FGF, HGF, GSK-3 reseptörlerini, Protein Kinaz C, Aurora Kinaz ve Hsp90 aktivitesini inhibe etmeye yönelik geliştirilen birçok molekül klinik çalışma aşamasındadır.

Keywords

Kanser, Kemoterapi, Sinyal yolakları, Hedefe yönelik tedavi, Protein kinaz inhibitörleri

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