Inhibitors and PROTACs of CDK2: challenges and opportunities.

INTRODUCTION: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors. AREA COVERED: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments. EXPERT OPINION: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective.

Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

Overview of the development of protein arginine methyltransferase modulators: Achievements and future directions.

Protein methylation is a post-translational modification (PTM) that organisms undergo. This process is considered a part of epigenetics research. In recent years, there has been an increasing interest in protein methylation, particularly histone methylation, as research has advanced. Methylation of histones is a dynamic process that is subject to fine control by histone methyltransferases and demethylases. In addition, many non-histone proteins also undergo methylation, and these modifications collectively regulate physiological phenomena, including RNA transcription, translation, signal transduction, DNA damage response, and cell cycle. Protein arginine methylation is a crucial aspect of protein methylation, which plays a significant role in regulating the cell cycle and repairing DNA. It is also linked to various diseases. Therefore, protein arginine methyltransferases (PRMTs) that are involved in this process have gained considerable attention as a potential therapeutic target for treating diseases. Several PRMT inhibitors are in phase I/II clinical trials. This paper aims to introduce the structure, biochemical functions, and bioactivity assays of PRMTs. Additionally, we will review the structure-function of currently popular PRMT inhibitors. Through the analysis of various data on known PRMT inhibitors, we hope to provide valuable assistance for future drug design and development.

Development of MPS1 Inhibitors: Recent Advances and Perspectives.

Monopolar spindle kinase 1 (MPS1) plays a pivotal role as a dual-specificity kinase governing spindle assembly checkpoint activation and sister chromatid separation in mitosis. Its overexpression has been observed in various human malignancies. MPS1 reduces spindle assembly checkpoint sensitivity, allowing tumor cells with a high degree of aneuploidy to complete mitosis and survive. Thus, MPS1 has emerged as a promising candidate for cancer therapy. Despite the identification of numerous MPS1 inhibitors, only five have advanced to clinical trials with none securing FDA approval for cancer treatment. In this perspective, we provide a concise overview of the structural and functional characteristics of MPS1 by highlighting its relevance to cancer. Additionally, we explore the structure-activity relationships, selectivity, and pharmacokinetics of MPS1 inhibitors featuring diverse scaffolds. Moreover, we review the reported work on enhancing MPS1 inhibitor selectivity, offering valuable insights into the discovery of novel, highly potent small-molecule MPS1 inhibitors.

Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer.

Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound Z11, a potent CDK9 inhibitor (IC50 = 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore, Z11 demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall, Z11 served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.

Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy.

CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate cancer therapy.

Effectiveness of vagus nerve stimulation for drug-resistant generalized epilepsy in children aged six and younger.

BACKGROUND: To explore a novel scoring system to evaluate the efficacy of vagus nerve stimulation (VNS) in children with drug-resistant generalized epilepsy (DRGE) aged six and younger. BASIC PROCEDURES: The data of twelve children with DRGE under the age of 6 years who accepted VNS and have been followed up for at least 3 years were retrospectively reviewed. The outcome was evaluated with the McHugh Classification System and a novel scoring system we proposed. MAIN FINDINGS: Based on the McHugh Classification System, the total response rate was 91.67% (11/12) and the rate of Grade I was 41.67% (5/12). A novel scoring system involving seizure frequency, seizure duration and quality of life (QOL) was proposed, by which the outcome was scored from -3 to 11 and graded from IV to I. Based on the novel scoring system, the total response rate was 91.67% (11/12) and the rate of Grade I was 33.33% (4/12). The incidence of complication was 16.67% (2/12). The efficacy of VNS appeared a gradually improving trend with plateau or fluctuation over time. Shorter course of epilepsy prior to VNS may be related to better outcome. PRINCIPAL CONCLUSIONS: VNS could effectively reduce the seizure frequency and improve the QOL of children with DRGE aged six and younger. The novel scoring system was comprehensive and feasible to evaluate the efficacy of VNS. The time pattern of the long-term efficacy of VNS requires further investigation.

Design and optimization of selective and potent CDK9 inhibitors with flavonoid scaffold for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC50 = 6.7 nM), exhibiting over 80-fold selectivity towards most other CDK family members and high kinase selectivity. In Mv4-11 cells, 21a effectively hindered cell proliferation (IC50 = 60 nM) and induced apoptosis by down-regulating Mcl-1 and c-Myc. Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.

A patent review of selective CDK9 inhibitors in treating cancer.

INTRODUCTION: The dysregulation of CDK9 protein is greatly related to the proliferation and differentiation of various cancers due to its key role in the regulation of RNA transcription. Moreover, CDK9 inhibition can markedly downregulate the anti-apoptotic protein Mcl-1 which is essential for the survival of tumors. Thus, targeting CDK9 is considered to be a promising strategy for antitumor drug development, and the development of selective CDK9 inhibitors has gained increasing attention. AREAS COVERED: This review focuses on the development of selective CDK9 inhibitors reported in patent publications during the period 2020-2022, which were searched from SciFinder and Cortellis Drug Discovery Intelligence. EXPERT OPINION: Given that pan-CDK9 inhibitors may lead to serious side effects due to poor selectivity, the investigation of selective CDK9 inhibitors has attracted widespread attention. CDK9 inhibitors make some advance in treating solid tumors and possess the therapeutic potential in EGFR-mutant lung cancer. CDK9 inhibitors with short half-life and intravenous administration might result in transient target engagement and contribute to a better safety profile in vivo. However, more efforts are urgently needed to accelerate the development of CDK9 inhibitors, including the research on new binding modes between ligand and receptor or new protein binding sites.

Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer.

Prostate cancer (PC) is one of the most prevalent cancers in men worldwide, and androgen receptor (AR) is a well-validated drug target for the treatment of PC. However, PC often exhibits resistance to AR antagonists over time. Thus, it is urgent to identify novel and effective drugs for PC treatment. A series of novel thiohydantoin based AR antagonists with efficient degradation against AR were designed, synthesized, and evaluated. Based on our previous SAR and further structural optimization, a tool molecule 26h was discovered with dual mechanisms including improved antagonistic activity and potent degradation (AR-fl and AR-V7). Moreover, 26h can also effectively block AR nuclear translocation and inhibit AR/AR-V7 heterodimerization, thereby inhibiting downstream gene transcription. Importantly, 26h displayed potent robust efficacy in LNCaP (TGI: 70.70%) and 22Rv1 (TGI: 78.89%) xenograft models. This provides new design strategies and advantageous potential compounds for the treatment of prostate cancer.

Design, synthesis, and biological evaluation of novel glutaminase 1 allosteric inhibitors with an alkane chain tail group.

Tumor cells often exhibit metabolic reprogramming to maintain their rapid growth and proliferation. Glutaminase 1 (GLS1) has been viewed as a promising target in the glutamine metabolism pathway for the treatment of malignant tumors. Using structure-based drug design approaches, a novel series of GLS1 allosteric inhibitors were designed and synthesized. Compound 41a (LWG-301) with an alkane chain "tail" group had potent biochemical and cellular GLS1 activity, and improved metabolic stability. LWG-301 exhibited moderate antitumor effects in HCT116 xenograft model, with TGI of 38.9% in vivo. Mechanistically, LWG-301 could significantly block glutamine metabolism, resulting in changes in the corresponding amino acid levels in cells, induce a concentration-dependent increase in intracellular ROS levels, and induce apoptosis. Taken together, this paper provides more structural references and new design strategy for the development of GLS1 allosteric inhibitors.

Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression.

Ubiquitin-specific protease 8 (USP8), belonging to the deubiquitinase family, has been implicated to be closely related to the occurrence of many malignant tumors, but only a few USP8-targeting inhibitors have been reported to date. In this study, we present virtual screening to discover novel hit candidates that inhibit the catalytic activity of USP8. Exploration of the structure-activity relationship led to the identification of compound DC-U4106, which binds to USP8 with a KD value of 4.7 µM and is selective over USP2 and USP7. Western blotting and immunoprecipitation showed that DC-U4106 could target the ubiquitin pathway and facilitate the degradation of ERα. In a xenograft tumor model, DC-U4106 also significantly inhibited tumor growth with minimal toxicity. Overall, our findings suggest that DC-U4106 is a promising drug candidate and targeting the USP8-ERα complex could be a new approach to treat ER-positive or drug-resistant breast cancer.

Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles.

Glutaminase 1 (GLS1) is overexpressed in multiple types of malignant tumors and is viewed as a promising target in cancer therapy. Thus, the discovery for small-molecule GLS1 inhibitors is being urgent. Based on our previous study of C147, a potent GLS1 allosteric inhibitor yet with a limited metabolic stability, a structure-based optimization was carried out, with a series of novel GLS1 allosteric inhibitors rationally designed, synthesized and biologically evaluated. Such endeavor has culminated in the identification of 41e, a promising GLS1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles. 41e displayed robust GLS1 binding affinity, superior liver microsome metabolic stability, and moderate anti-tumor activity (TGI: 47.5%) in HCT116 xenograft model with no considerable toxicity in vivo. The mechanism underlying the anti-proliferative effect of 41e on HCT116 cells was studied, revealing that the compound blocked the glutamine metabolism, induced the production of ROS, and triggered apoptosis. These findings merit further investigation of 41e as a targeted cancer therapeutic.

Inhibition of FAM83D displays antitumor effects in glioblastoma via down-regulation of the AKT/Wnt/ß-catenin pathway.

Up-regulation of family with sequence similarity 83 member D (FAM83D) has been acknowledged as a vital contributor for the carcinogenesis of numerous cancers. The relevance of FAM83D in glioblastoma (GBM), however, is not well understood. This current work aimed to determine the possible roles and mechanisms of FAM83D in GBM. By analyzing The Cancer Genome Atlas (TCGA) data, we found dramatic increases in FAM83D expression in GBM tissue. We also observed elevated levels of FAM83D in the clinical specimens of GBM. In vitro data showed that silencing FAM83D resulted in remarkable antitumor effects via inhibiting the proliferation, invasion and epithelial-mesenchymal transition of GBM cells. Moreover, the knockdown of FAM83D improved sensitivity to the chemotherapy drug temozolomide. In-depth mechanism research revealed that the silencing of FAM83D strikingly decreased the phosphorylation levels of AKT and glycogen synthase kinase-3ß, and prohibited activation of the Wnt/ß-catenin pathway. The suppression of AKT abolished FAM83D-mediated activation of the Wnt/ß-catenin pathway. The re-expression of ß-catenin reversed FAM83D-silencing-induced antitumor effects in GBM cells. In addition, GBM cells with FAM83D silencing exhibited reduced tumorigenic potential in vivo. Overall, the data from this work show that the inhibition of FAM83D displays antitumor effects in GBM via down-regulation of the AKT/Wnt/ß-catenin pathway and propose FAM83D as a new therapeutic target for GBM.

Ivermectin accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation.

OBJECTIVE: This study aimed to investigate the regulatory effect of ivermectin (IVM) on energy metabolism in glioma progression, and provide a reference for the treatment of glioma. METHODS: Glioma cells were treated with IVM to measure cell viability, autophagy marker protein expression, ATP content, glucose uptake, pyruvate content, and expression of key enzymes of glycolysis. Glucose transporter 4 (GLUT4) or siGLUT4 was transfected in IVM treated U87 cells to investigate the effect of GLUT4 on cellular glycolysis and autophagy. The JAK2 inhibitor AZD-1480 was introduced to explore the specific mechanism by which IVM regulates glycolysis and autophagy. Rat models of glioma xenograft were constructed and treated with 10 mg/kg IVM to observe tumor growth and examine the expression levels of GLUT4 and autophagy marker proteins in tumor tissues. RESULTS: IVM inhibited glioma cell survival and promoted cell death. IVM promoted LC3-II protein expression and inhibited p62/SQSTM1 protein expression in glioma cells. IVM decreased adenosine-triphosphate (ATP) and pyruvate content, promoted glucose uptake, and reduced HK2 and PFK1 protein expression in U87 cells. IVM inhibited GLUT4 protein expression, and overexpression of GLUT4 promoted glycolysis and inhibited autophagic cell death in U87 cells. IVM inhibited glycolysis by blocking GLUT4 mediated the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway activation. IVM inhibited tumor growth in vivo, decreased the protein expression of GLUT4, JAK2, HK2, and PFK1 in tumor tissues, decreased the phosphorylation levels of STAT3/STAT5, and promoted the expression of autophagy marker proteins. CONCLUSIONS: IVM accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation.

CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma.

Mitophagy is a type of selective macroautophagy/autophagy that degrades dysfunctional or excessive mitochondria. Regulation of this process is critical for maintaining cellular homeostasis and has been closely implicated in acquired drug resistance. However, the regulatory mechanisms and influences of mitophagy in cancer are still unclear. Here, we reported that inhibition of CDK9 blocked PINK1-PRKN-mediated mitophagy in HCC (hepatocellular carcinoma) by interrupting mitophagy initiation. We demonstrated that CDK9 inhibitors promoted dephosphorylation of SIRT1 and promoted FOXO3 protein degradation, which was regulated by its acetylation, leading to the transcriptional repression of FOXO3-driven BNIP3 and impairing the BNIP3-mediated stability of the PINK1 protein. Lysosomal degradation inhibitors could not rescue mitophagy flux blocked by CDK9 inhibitors. Thus, CDK9 inhibitors inactivated the SIRT1-FOXO3-BNIP3 axis and PINK1-PRKN pathway to subsequently block mitophagy initiation. Moreover, CDK9 inhibitors facilitated mitochondrial dysfunction. The dual effects of CDK9 inhibitors resulted in the destruction of mitochondrial homeostasis and cell death in HCC. Importantly, a novel CDK9 inhibitor, oroxylin A (OA), from Scutellaria baicalensis was investigated, and it showed strong therapeutic potential against HCC and a striking capacity to overcome drug resistance by downregulating PINK1-PRKN-mediated mitophagy. Additionally, because of the moderate and controlled inhibition of CDK9, OA not led to extreme repression of general transcription and appeared to overcome the inconsistent anti-HCC efficacy and high normal tissue toxicity that was associated with existing CDK9 inhibitors. All of the findings reveal that mitophagy disruption is a promising strategy for HCC treatment and OA is a potential candidate for the development of mitophagy inhibitors.Abbreviations: BNIP3: BCL2 interacting protein 3; CCCP: carbonyl cyanide p-trichloromethoxy-phenylhydrazone; CDK9: cyclin dependent kinase 9; CHX: cycloheximide; CQ, chloroquine; DFP: deferiprone; DOX: doxorubicin; EBSS: Earle's balanced salt solution; E64d: aloxistatin; FOXO3: forkhead box O3; HCC: hepatocellular carcinoma; HepG2/ADR: adriamycin-resistant HepG2 cells; MMP: mitochondrial membrane potential; mito-Keima: mitochondria-targeted and pH-sensitive fluorescent protein; MitoSOX: mitochondrial reactive oxygen species; OA: oroxylin A; PB: phosphate buffer; PDX: patient-derived tumor xenograft; PINK1: PTEN induced kinase 1; POLR2A: RNA polymerase II subunit A; p-POLR2A-S2: Ser2 phosphorylation of RNA polymerase II subunit A; PRKN: parkin RBR E3 ubiquitin protein ligase; SIRT1: sirtuin 1.

Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning.

EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized via a four-step synthesis with high purity of 99.9%. The hydroxylamination procedure was telescoped in a one-pot and the final step was precisely controlled on reagents, temperature and reaction time. Compared to the original route, the yield of the new route was enhanced from 17% to 58% without column chromatography. The optimized synthesis has been successfully determinated on a decagram scale: the first step at 200 g and the final step at 20 g. Besides, the relationship between yield and temperature, time, and reagents in the deprotection step was investigated via Shapley value explanation and machine learning approach-decision tree method. The results revealed that reagents have the greatest impact on yield estimation, followed by the temperature.

Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site.

The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2.

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.

Identification of novel androgen receptor degrading agents to treat advanced prostate cancer.

Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.