As part of the project, it is planned to develop and develop an innovative candidate for a drug that induces the degradation of the MCL-1 protein on the proteasome route. The anti-apoptotic MCL-1 protein is a member of the Bcl-2 protein family, which is overexpressed in many types of cancer. Overproduction of MCL-1 disrupts the balance of anti- and pro-apoptotic proteins, among other things, and is an important survival factor for cancer. In addition, tumor cell lines are subject to clonal selection for cells with elevated levels in MCL-1, resulting in resistance to chemo- and targeted therapies. Lowering MCL-1 levels by antisense or siRNA therapies confirms the oncogenic role of this protein and opens up new opportunities for targeted cancer therapies. The drug candidate, developed as part of this project, will induce MCL-1 ubiquitination and then its proteasome degradation, which will lead to a therapeutic effect. The innovation of targeted protein degradation makes it possible to remove all the functions that determine the development of the disease, which in the case of MCL-1 protein degradation is the complete opposite of the pharmacology of inhibitors of this molecular target. Inhibition of MCL-1, in addition to blocking only the antiapoptotic role, additionally leads to its strong accumulation in cells, thus hindering the dosage of the drug and leading to the formation of serious side effects. In the first phase of the project, a new class of small-molecule MCL-1 degraders was developed.The synthesized compounds were characterized on an ongoing basis by biophysical tests, including FP, SPR, HTRF, and used in crystallography. The activity of degraders in cellular systems was assessed using, among others, the viability test, the plate caspase activity measurement test, NanoBRET permeabilization assessment tests, and the Western Blotting degradation test. The potential of selected compounds was assessed in animal and human primary cells, i.e. in leukocytes isolated from the blood. ADME and pharmacokinetic studies were also conducted, which allowed to determine the key parameters of compounds in vivo and ex vivo systems. The safety of the selected compounds was pre-assessed using genotoxicity tests, the ability to inhibit the activity of CYP protein family enzymes, the effects on the most likely off-targets and the identification of metabolites. A preliminary assessment of cardiotoxicity was also performed in vitro and in vivo during toxicological studies involving the determination of the maximum tolerable dose (MTD) in rats and monkeys. The pharmacodynamic effect and effectiveness of selected compounds were determined in in vivo models - in mice with implanted human cancer cells. The second phase of the project will consist of: supplementing safety pharmacology and toxicology data for the GLP candidate. In vitro tests will be carried out: hERG and 3T3 NRU, as well as 28-day in vivo studies in the GLP standard - both on rodent species and a higher species, with assessment of: mortality, clinical symptoms, changes in body weight, food consumption, clinical pathology, macroscopic organs, full histopathology, as well as assessment of potential cardiotoxicity (in the case of animals of a higher species). b) synthesis of the drug candidate on a kilogram scale in the GMP standard, together with the specification of the final product included in the analysis certificate made for it. The active compound produced on a kilogram scale in the GMP standard, in phase II of the project, will be purified using a previously developed crystallization method. The polymorphic form for the resulting crystalline form of the final batch of the active compound will also be confirmed, together with the measurement of the particle decomposition of the final product, and stability studies will be carried out. (c) preparation of the documentation of the new candidate compound necessary for the initiation of phase I clinical trials. (d) implementation of phase 1a clinical trials