However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and there would not be another attempt for nearly 20 years.While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, however the basic science and technology of the time was insufficient to understand and utilize this breakthrough. Brodies work using formalin-inactivated virus would later become the basis for the Salk vaccine, but he would not live to see this success. Brodie was fired from his position within three months of the symposiums publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors prior to his death in 1939. Kolmer, already an established and well respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks up until his retirement in 1957.
By inhibiting the XPO1 protein, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis. In vitro, this effect appeared to spare normal (non-malignant) cells.Inhibiting XPO1 affects many different cells in the body which may explain the incidence of adverse reactions to selinexor. Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets. Chemistry
Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is slowly reversible. History
Selinexor was developed by Karyopharm Therapeutics, a pharmaceutical company focused on the development of drugs that target nuclear transport. It was approved in the United States in July 2019, on the basis of a single-arm Phase IIb clinical trial. The FDA decided to grant accelerated approval despite a previous recommendation from an FDA Advisory Committee Panel which had voted 8–5 to delay approving the drug until the results from an ongoing Phase III study were known.Selinexor in combination with dexamethasone was granted accelerated approval and was granted orphan drug designation.