Tyrosine kinase, Aurora kinase and leucine aminopeptidase as attractive drug targets in anticancer therapy - characterisation of their inhibitors

• Autorzy: Ziemska J. , Solecka J.
• Języki publikacji: EN

Abstrakty

EN

Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.

PL

Nowotwory stanowią jedną z głównych przyczyn zgonów na świecie. Dostępne w lecznictwie substancje przeciwnowotworowe charakteryzują się niskim indeksem terapeutycznym jak i wysoką toksycznością. Rozwijająca się oporność komórek nowotworowych na dostępne w terapii leki przyczynia się do konieczności poszukiwania nowych punktów uchwytu/miejsc docelowych (z ang. targets) dla potencjalnych substancji przeciwnowotworowych. Obecnie prowadzonych jest również wiele prac nad nowymi związkami przeciwnowotworowymi o wysokim potencjale terapeutycznym, nowym mechanizmie działania i/bądź wyższym indeksie selektywności. W pracy, autorzy skupili uwagę na trzech grupach enzymów, będących obecnie w obszarze zainteresowań współczesnej medycyny. Omówione zostały kinazy tyrozynowe na przykładzie enzymów EGFR i Src, kinazy Aurora typu A, B i C, a także aminopeptydazy na przykładzie aminopeptydazy leucynowej. Scharakteryzowano klasyfikację enzymów, ich rolę w cyklu komórkowym w warunkach fizjologicznych i procesie nowotworowym. Opisano również inhibitory enzymów, substancje będące w trakcie badań in vitro, przedklinicznych i klinicznych jak i leki wprowadzone na rynek farmaceutyczny. Zwrócono uwagę na budowę chemiczną inhibitorów enzymów i tym samym na kierunek poszukiwań nowych leków przeciwnowotworowych. Omówione enzymy w warunkach fizjologicznych odgrywają ważną rolę w cyklu komórkowym, zwłaszcza na etapie podziału mitotycznego. Jednakże w procesie nowotworowym dochodzi do ich nadekspresji. Zjawisko to można zahamować poprzez inhibicję aktywności enzymu. Autorzy omówili wpływ inhibitorów kinaz tyrozynowych, kinaz Aurora czy aminopeptydaz leucynowych na cykl komórkowy i bezpieczeństwo stosowania tych potencjalnych leków u ludzi. Dotychczasowe badania przedkliniczne i kliniczne inhibitorów kinazy tyrozynowej typu EGFR czy Src potwierdziły konieczność selekcji pacjentów, na tych z mutacją w genie kodującym dany enzym. Badania prowadzone na wybranej grupie chorych przynosiły oczekiwany pozytywny wynik. Wiele aspektów dotyczących nowych punktów uchwytu w terapii przeciwnowotworowej wciąż wymaga dalszych prac, aczkolwiek daje również nadzieję na odkrycie skutecznych i selektywnych leków.

Słowa kluczowe

EN

tyrosine kinase; Aurora kinase; leucine aminopeptidase; drug; anticancer therapy; enzyme inhibitor

• Wydawca: -
• Czasopismo: Roczniki Państwowego Zakładu Higieny
• Rocznik: 2016
• Tom: 67
• Numer: 4
• Opis fizyczny: p.329-341,fig.,ref.

Twórcy

autor

Ziemska J.

• Laboratory of Biologically Active Compounds, National Institute of Public Health - National Institute of Hygiene, 24 Chocimska Str., 00-791 Warsaw, Poland

autor

Solecka J.

• Laboratory of Biologically Active Compounds, National Institute of Public Health - National Institute of Hygiene, 24 Chocimska Str., 00-791 Warsaw, Poland

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