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Development of p53 Small molecule activators to target multiple myeloma
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O mieloma múltiplo (MM) é um cancro raro do sangue que se desenvolve nas células plasmáticas da medula óssea. No MM, a proteína supressora tumoral p53 é inativada por reguladores negativos ou por mutação do seu gene. O desenvolvimento de pequenas moléculas capazes de reativar a p53 é altamente necessário. A ataxia telangiectasia e a proteína relacionada ao Rad3 (ATR) também são um alvo relevante no cancro, pois desempenham um papel em resposta aos danos que afetam o DNA.Nesta tese, foram sintetizados compostos híbridos, com o objetivo de atingir os alvos terapêuticos p53 e ATR. Novas oxazoloisoindolinonas derivadas de triptofanol foram sintetizadas com rendimentos de 11-67 % dado que este farmacóforo é capaz de reativar a p53 de tipo selvagem e mutante. (1) Para o farmacóforo inibidor de ATR, dois derivados de protoapigenona (inibidores de ATR) foram sintetizados com rendimentos de 25%. Sete novas moléculas híbridas foram preparadas com rendimentos de 27-57% com base nestes dois farmacóforos. Três linkers diferentes foram usados para conectar os dois farmacóforos. Os compostos híbridos foram testados em duas linhas celulares de MM, MM1S e RPMI8226, e numa linha celular de cancro do cólon, HCT116. Todos os híbridos apresentam maior atividade que os compostos isolados, indicando que existe vantagem na sua utilização. O composto mais ativo apresentou um valor de IC50 de 0,67 micromolar e 0,57 micromolar nas linhas celulares MM1S e RPMI8226, respetivamente, sendo menos ativo na linha celular de cancro do cólon HCT116 (IC50= 4,0 micromolar).
Multiple myeloma (MM) is a rare blood cancer that develops in plasma cells in the bone marrow. In MM, the tumor suppressor protein p53 is inactivated by negative regulators or by mutation of its gene. Developing small molecules able to reactivate p53 is highly needed. The ataxia telangiectasia and Rad3 related protein (ATR) is also a relevant target in cancer as it plays a role in the DNA damage response. In this thesis, hybrid compounds were designed and synthesized, with the goal of targeting the p53 and the ATR therapeutic targets. New tryptophanol-derived oxazoloisoindolinones were synthesized in yields of 11-67%, as this chemical scaffold is able to reactivate wild-type and mutant p53. (1) For the ATR inhibition, two protoapigenone derivatives (ATR inhibitors) were synthesized in yields of 25%. Seven new hybrid molecules, containing these two chemical scaffolds, were prepared in yields of 27-57%. Three different linkers were used to connect the two pharmacophores. The hybrid compounds were then tested in two MM cancer cell lines, MM1S and RPMI8226, and in a colon cancer cell line, HCT116. (2) All hybrids were more potent than the pharmacophores alone. The most active compound presented an IC50 value of 0.67 micromolar and 0.54 micromolar in MM1S and RPMI8226 cells lines, being less active in the colon cancer cell line (IC50= 4.0 micromolar).
Multiple myeloma (MM) is a rare blood cancer that develops in plasma cells in the bone marrow. In MM, the tumor suppressor protein p53 is inactivated by negative regulators or by mutation of its gene. Developing small molecules able to reactivate p53 is highly needed. The ataxia telangiectasia and Rad3 related protein (ATR) is also a relevant target in cancer as it plays a role in the DNA damage response. In this thesis, hybrid compounds were designed and synthesized, with the goal of targeting the p53 and the ATR therapeutic targets. New tryptophanol-derived oxazoloisoindolinones were synthesized in yields of 11-67%, as this chemical scaffold is able to reactivate wild-type and mutant p53. (1) For the ATR inhibition, two protoapigenone derivatives (ATR inhibitors) were synthesized in yields of 25%. Seven new hybrid molecules, containing these two chemical scaffolds, were prepared in yields of 27-57%. Three different linkers were used to connect the two pharmacophores. The hybrid compounds were then tested in two MM cancer cell lines, MM1S and RPMI8226, and in a colon cancer cell line, HCT116. (2) All hybrids were more potent than the pharmacophores alone. The most active compound presented an IC50 value of 0.67 micromolar and 0.54 micromolar in MM1S and RPMI8226 cells lines, being less active in the colon cancer cell line (IC50= 4.0 micromolar).
Descrição
Tese de mestrado, Química Medicinal e Biofarmacêutica, 2025, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Multiple myeloma p53 ATR Hybrids Cancer Teses de mestrado - 2025