Research And Development Of Anti-prostate Cancer Drugs Based On ODM-201 Structure

Prostate cancer(PC)is the most common malignant tumor of the male genitourinary system.After patients receive Androgen deprivation therapy(ADT),their diseases will often develop to the castration resistance stage,which is life-threatening.Anti-androgen drugs are currently the most important and effective method for the treatment of Castration-Resistant prostate cancer(CRPC).However,most of the patients will develop drug resistance after taking the drug for a period of time,and the research on the drug resistance mechanism is gradually deepening.At present,down-regulation,degradation of AR and AR-V7 variable splicesis the main means to overcome drug resistance.Constantly developing new drugs and giving patients more hope of survival is an urgent problem to be solved at the moment.ODM-201 has a unique structure and has good in vitro anti-cell proliferation and anti-tumor activities.It binds to AR with high affinity,blocks nuclear translocation,and competitively inhibits the binding of androgens to receptors,and has a significant inhibitory effect forenzalutamide-resistant AR mutant.After long-term clinical trials,ODM-201 has been approved by the FDA and become a promising second-generation anti-androgen drug.At present,there are not few studies on its chemical synthesis or optimization..In this work,we firstly focuses on the structure of ODM-201,optimizes the synthesis route,and synthesizes 37 analogues of ODM-201 according to this route,half of which have equivalent or stronger active comparing to that of ODM-201.Combining the existing literature and studying its structure-activity relationship,it preliminarily proves the importance of-F on the A ring.At the same time,the retention of the aromatic ring in the D ring and the expansion of the large π bond have a positive effect on the activity.The steric hindrance hinders the conformation of the amide bond.Moreover,hydrophobic tagging technology(Hydrophobic tagging,HyT)attaches large hydrophobic groups to the surface of the target protein,inducing the protein to be unstable and degraded by the proteasome.Proteolysis Targeting Chimera(PROTAC)utilizes the ubiquitin-proteasome pathway of eukaryotic cells.In theory,it is possible to design any intracellular protein to ubiquitinate to achieve degradation.This topic uses the induction of protein degradation as a drug development strategy,using ODM-201 and its analogues as target protein ligands,using two general technologies to synthesize a new type of AR degradation agent to overcome anti-androgen drug resistance.Firstly,the E3 ligase ligand VHL032 and a series of linkers with different compositions and lengths were synthesized,and a total of 13 PROTACs in three series were obtained.Based on the above work and the use of amantadine and amantadine formic acid,two series of HyT analogues(12 compounds)were prepared.These compounds can show better inhibitory activity at low concentrations,indicating the characteristics of this type of bifunctional small molecule degrading agent in a catalytic amount.Current work provides a new strategy in the optimization of ODM-201 and sheds light on the development of anti-Castration-Resistant prostate cancer drugs.