New selective HDAC Inhibitors class I and PROTACs: evaluation of the ability to induce gamma globin in vivo and in vitro

• Grant number: 23/01293-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2023
• End date: March 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Victor Gabriel de Faria Pastre
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

Sickle cell anemia (FA) is a hereditary disease that causes deformation of erythrocytes, giving them, after releasing oxygen, the shape of a sickle, making them rigid and can cause obstruction of blood vessels, since erythrocytes under normal conditions They have elasticity and discoid shape. Currently, hydroxyurea (HU) is the most important drug approved by the FDA for the treatment of AF and is responsible for increasing the expression of fetal hemoglobin (HbF) and reducing clinical complications. Thus, the development of compounds that increase HbF levels has been a current therapeutic strategy. In addition to the drugs available on the market, new compounds are being developed for the treatment of AF. These compounds add several functions: they act as analgesics and donate nitric oxide. An example is the thalidomide + HU hybrid (compound 4C) which was able to increase HbF levels in FA transgenic mice, as well as to show in vitro anti-inflammatory activity. The present study aims to evaluate the gamma globin induction capacity of molecules that show greater selectivity for HDAC inhibition and PROTAC compounds whose potential to induce HbF is based on HDAC degradation. These new molecules will be synthesized in collaboration with Dr. Jean L. Santos (Lapdesf - Unesp) and his activities will be evaluated through in vitro and in vivo experiments. In the present study, the new compounds obtained from molecular modification strategies may allow obtaining safer and more effective molecules for the treatment of hemoglobinopathies. (AU)