ANTİKANSER ETKİLİ MATRİKS METALLOPROTEİNAZ ENZİM İNHİBİTÖRLERİ

Öz

Amaç: Matriks metalloproteinazların (MMP’ler) yapısı, işlevi ve özgül aktiviteleri hakkında güncel bilgileri sunmak; özellikle MMP-2 ve MMP-9 olarak bilinen jelatinazların kanser gelişimi, anjiyogenez, tümör invazyonu ve metastaz oluşturmadaki rolleri doğrultusunda antikanser terapötik hedefler olarak önemini vurgulamaktır. Ayrıca, sentetik MMP inhibitörleri başta olmak üzere jelatinaz inhibitörlerinin tasarımı, geliştirilmesi ve seçicilik stratejilerinin değerlendirilmesi amaçlanmıştır.

Sonuç ve Tartışma: MMP’ler, hücre dışı matriksin yapısal bileşenlerini parçalayarak doku yeniden şekillenmesi, yara iyileşmesi ve anjiyogenez gibi birçok fizyolojik ve patolojik süreçte rol oynayan metalloproteinazlar ailesine ait enzimlerdir. Jelatinazlar olarak sınıflandırılan MMP-2 ve MMP-9’un çeşitli malignitelerde aşırı ekspresyon göstermesi, bu enzimleri önemli terapötik hedefler haline getirmiştir. İlk kuşak MMP inhibitörleri; hidroksamik asit, tiyol, karboksilat, fosfonat veya azot içeren heterosiklik yapılarda çinko bağlayıcı gruplar (ZBG) taşıyan bileşiklerden oluşmuştur. Hidroksamat bazlı inhibitörler güçlü çinko şelatlama özellikleri ve geniş spektrumlu etkileriyle öne çıkmış; ancak seçicilik eksikliği ve kas-iskelet sistemi toksisitesi gibi klinik sınırlamalar, ZBG içermeyen inhibitörler ile mekanizma temelli ve allosterik inhibisyon yaklaşımlarının geliştirilmesini teşvik etmiştir. Yapısal çalışmalar, özellikle S1′ alt cebinin seçiciliğin belirlenmesindeki kilit rolünü ortaya koymuş ve jelatinazlara özgü dar spektrumlu inhibitörlerin rasyonel tasarımına yön vermiştir. Ayrıca protein mühendisliği, antikor temelli inhibitörler ile TIMP ve pro-domain benzeri biyolojik ajanlar, seçiciliği ve biyouyumluluğu artıran yeni nesil yaklaşımlar arasında yer almaktadır.

Anahtar Kelimeler

• Antikanser aktivite
• çinko (II) bağlama grubu
• hidroksamik asit
• jelatinaz inhibitörleri
• matriks metalloproteinaz

MATRIX METALLOPROTEINASE INHIBITORS WITH ANTICANCER ACTIVITY

Öz

Objective: To provide up-to-date information on the structure, function, and specific activities of matrix metalloproteinases (MMPs), with particular emphasis on gelatinases MMP-2 and MMP-9 as anticancer therapeutic targets due to their roles in cancer development, angiogenesis, tumor invasion, and metastasis. Additionally, this review evaluates the design, development, and selectivity strategies of gelatinase inhibitors, focusing primarily on synthetic MMP inhibitors.

Result and Discussion: MMPs are enzymes belonging to the metalloproteinase family that participate in numerous physiological and pathological processes, including tissue remodeling, wound healing, and angiogenesis, by degrading structural components of the extracellular matrix. The overexpression of gelatinases MMP-2 and MMP-9 in various malignancies has rendered these enzymes significant therapeutic targets. First-generation MMP inhibitors consisted of compounds bearing zinc-binding groups (ZBGs), such as hydroxamic acid, thiol, carboxylate, phosphonate, or nitrogen-containing heterocyclic structures. Hydroxamate-based inhibitors emerged as prominent candidates in early studies due to their strong zinc-chelating properties and broad-spectrum activity; however, clinical limitations, including lack of selectivity and musculoskeletal toxicity, have driven the development of alternative approaches, such as ZBG-free inhibitors and mechanism-based or allosteric inhibition strategies. Structural studies have revealed the critical role of the S1′ subsite in determining selectivity, thereby guiding the rational design of narrow-spectrum, gelatinase-selective inhibitors. Furthermore, protein engineering approaches, antibody-based inhibitors, and biological agents such as TIMPs and pro-domain-like molecules represent next-generation strategies that enhance selectivity and biocompatibility.

Anahtar Kelimeler

• Anticancer activity
• gelatinase inhibitors
• hydroxamic acid
• matrix metalloproteinase
• zinc (II) binding group

Kaynakça

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