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Small-molecule kinase inhibitors in cancer treatment
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O cancro é uma das principais causas de mortalidade a nível mundial, o que impulsiona a necessidade contínua de estratégias terapêuticas mais eficazes. As cinases, enquanto reguladoras da proliferação celular, sobrevivência e apoptose, tornaram-se alvos importantes em diversos tipos de cancro. A síntese de pequenas moléculas inibidoras de cinases transformou significativamente o tratamento oncológico, particularmente no âmbito da terapêutica dirigida. Estes agentes oferecem maior especificidade e menor toxicidade sistémica em comparação com a quimioterapia tradicional. No entanto, apesar das suas vantagens, os inibidores de cinases continuam a apresentar limitações. Podem ocorrer efeitos adversos e o aparecimento de resistência adquirida aos fármacos constitui um desafio clínico significativo. Assim, o desenvolvimento contínuo de novos inibidores é essencial para superar os mecanismos de resistência e melhorar os resultados terapêuticos a longo prazo. A atividade desregulada das cinases está implicada em diversos tipos de cancro, incluindo cancro do pulmão de não pequenas células, cancro da mama, leucemia mieloide crónica, cancro colorretal, carcinoma de células renais, entre outros. Esta desregulação pode resultar de vários fatores. Por exemplo, translocações cromossómicas estão presentes na fusão génica BCR-ABL na leucemia mieloide crónica e no cancro do pulmão de não pequenas células ALK-positivo. As mutações pontuais também contribuem significativamente, como é o caso da mutação BRAF V600E, frequentemente observada no melanoma e no cancro colorretal, e da mutação EGFR T790M, comum no cancro do pulmão de não pequenas células. Para enfrentar estes problemas, estão a ser desenvolvidos inibidores de nova geração, muitos dos quais demonstraram resultados promissores em estudos pré-clínicos e ensaios clínicos. Neste trabalho, é apresentada uma revisão abrangente de diversos inibidores de cinases, com foco principal nos inibidores de proteínas cinases — nomeadamente, os inibidores de tirosina cinase e de serina/treonina cinase — incluindo também exemplos representativos de inibidores de cinases lipídicas, como os dirigidos à PI3K. Esta revisão destaca aspetos fundamentais como os mecanismos de ligação destes inibidores aos seus alvos, características estruturais essenciais à sua atividade, efeitos adversos associados e as suas aplicações clínicas em diferentes tipos de cancro.
Cancer is one of the leading causes of mortality worldwide, driving the continuous need for more effective therapeutic strategies. Kinases, as regulators of cell proliferation, survival and apoptosis, have become important targets in various cancer types. The synthesis of small-molecule kinase inhibitors has significantly transformed cancer treatment, particularly in the realm of targeted therapy. These agents offer improved specificity and reduced systemic toxicity compared to traditional chemotherapy. However, despite their advantages, kinase inhibitors still have limitations. Toxic effects may still occur, and the emergence of acquired drug resistance is a major clinical challenge. As a result, the ongoing development of novel inhibitors is essential to overcome resistance mechanisms and improve long-term treatment outcomes. Dysregulated kinase activity is implicated in numerous cancers, including non-small cell lung cancer, breast cancer, chronic myeloid leukemia, colorectal cancer, renal cell carcinoma, among others. This dysregulation can be caused by various factors. For instance, chromosomal translocations are present in BCR-ABL fusion gene in chronic myeloid leukemia and in ALK-positive non-small cell lung cancer. Point mutations also contribute significantly, including the BRAF V600E mutation frequently observed in melanoma and colorectal cancer and the EGFR T790M mutation, commonly found in non-small cell lung cancer. To address these problems, next-generation inhibitors are being developed, many of which have demonstrated promising results in preclinical studies and clinical trials. In this work, we present a comprehensive review of various kinase inhibitors, focusing primarily on protein kinase inhibitors—specifically tyrosine kinase and serine/threonine kinase inhibitors—while also including examples of lipid kinase inhibitors, such as those targeting PI3K. The review highlights key aspects such as the binding mechanisms of these inhibitors to their targets, structural characteristics essential for their activity, associated adverse effects and their clinical applications across different cancer types.
Cancer is one of the leading causes of mortality worldwide, driving the continuous need for more effective therapeutic strategies. Kinases, as regulators of cell proliferation, survival and apoptosis, have become important targets in various cancer types. The synthesis of small-molecule kinase inhibitors has significantly transformed cancer treatment, particularly in the realm of targeted therapy. These agents offer improved specificity and reduced systemic toxicity compared to traditional chemotherapy. However, despite their advantages, kinase inhibitors still have limitations. Toxic effects may still occur, and the emergence of acquired drug resistance is a major clinical challenge. As a result, the ongoing development of novel inhibitors is essential to overcome resistance mechanisms and improve long-term treatment outcomes. Dysregulated kinase activity is implicated in numerous cancers, including non-small cell lung cancer, breast cancer, chronic myeloid leukemia, colorectal cancer, renal cell carcinoma, among others. This dysregulation can be caused by various factors. For instance, chromosomal translocations are present in BCR-ABL fusion gene in chronic myeloid leukemia and in ALK-positive non-small cell lung cancer. Point mutations also contribute significantly, including the BRAF V600E mutation frequently observed in melanoma and colorectal cancer and the EGFR T790M mutation, commonly found in non-small cell lung cancer. To address these problems, next-generation inhibitors are being developed, many of which have demonstrated promising results in preclinical studies and clinical trials. In this work, we present a comprehensive review of various kinase inhibitors, focusing primarily on protein kinase inhibitors—specifically tyrosine kinase and serine/threonine kinase inhibitors—while also including examples of lipid kinase inhibitors, such as those targeting PI3K. The review highlights key aspects such as the binding mechanisms of these inhibitors to their targets, structural characteristics essential for their activity, associated adverse effects and their clinical applications across different cancer types.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2025, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
204204755 Small-molecule kinase inhibitors Targeted therapy Chemotherapy Drug resistance Protein kinases Mestrado integrado - 2025