Periodic Reporting for period 1 - PAC Synthesis (Synthesis of PROTAC-Antibody Conjugate for Application in Acute Myeloid Leukemia Therapy)
Berichtszeitraum: 2020-05-01 bis 2022-04-30
Specific targeting of disease related cells, while sparing healthy tissue, is one of the main goals in medicinal chemistry. The developed conjugates should bring society closer to reach this aim and find a cure for different kind of diseases, by addressing the problem of the unmet need for specific and targeted degradation of disease causing biomolecules. The more specific a drug acts the less side effects occur, thus the well-being of the patients during treatment is increased. In conclusion the overall objective is to develop a specific degrader of disease related biomolecules, that is conjugated to an antibody for targeted delivery, to improve the effect of the treatment and well-being of patients.
During the first period a number of protein degradation imposing molecules have been designed and synthesized. The primary activity test was done on the bacterial ribosome, due to its availability and less complicated handling. It gave low degradation activity for the ribosomal peptidic area, but showed great results on the ribosomal RNA, which showed complete degradation, despite under stoichiometric concentrations. In the next step the degrader was coupled with a binder moiety to see if the proximity to the target increases the effect. The results obtained are of broad interest to the medicinal chemistry society, their publication is work in progress.
The state of the art is currently limited to PROTACS, molecules that degrade proteins of interest (POI) by bringing them into close proximity to the E3 ligase of the ubiquitination degradation pathway. Here I have made progress beyond this by developing and showing that biomolecules can be specifically degraded by designed warheads, without the need to recruit the E3 ligase system. The approach is independent of the natural degradation pathway, through its inherent small molecule warhead that is acting by producing active oxygen species in close proximity to the targeted biomolecules.