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Development of small molecule epigenetic therapeutics for prostate cancer

前列腺癌小分子表观遗传学疗法的开发

基本信息

批准号：
10254491
负责人：
JUNG-MO AHN
金额：
$ 40万
依托单位：
RAPHAEL PHARMACEUTICALS LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254491
关键词：
Address Alternative Splicing Androgen Receptor Appearance Binding Proteins Biological Assay Biological Markers Caco-2 Cells Cancer Patient Castration Cell Cycle Progression Cell Line Cells Chemicals Clinical Computer Analysis Cytochrome P450 Development Disease Disease Progression Drug Delivery Systems Drug Formulations Drug Kinetics Drug Targeting Drug resistance Early Diagnosis Epigenetic Process Epithelial Excretory function Future Gene Activation Gene Expression Generations Genetic Glucocorticoid Receptor Growth Healthcare Systems Hela Cells Histones Hormones Human In Vitro LNCaP Lead Legal patent Ligand Binding Domain Lysine MYBL2 gene Malignant neoplasm of prostate Metabolic Metabolism Metastatic Prostate Cancer Metastatic/Recurrent Mus Neuroendocrine Cell Neuroendocrine Prostate Cancer Neurosecretory Systems Oncology Outcome PC3 cell line Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Plasma Proteins Prevalence Prognosis Property Prostate Public Health RB1 gene Receptor Signaling Recurrence Research Resistance Role Route Signal Pathway Structure Subgroup TP53 gene Testing Therapeutic Variant Xenograft Model Xenograft procedure absorption analog androgen sensitive base cancer diagnosis cancer type castration resistant prostate cancer cdc Genes cell growth chemical synthesis clinical development design drug candidate drug discovery druggable target effective therapy efficacy testing genetic signature high risk improved in vivo inhibitor/antagonist lead optimization men nanomolar pharmacodynamic model pharmacokinetics and pharmacodynamics phase 2 study prostate cancer cell prostate cancer model prostate cancer progression prototype receptor resistance mechanism response small molecule small molecule therapeutics success targeted agent targeted treatment therapeutic target transcriptome sequencing transdifferentiation tumor tumorigenesis virtual screening

项目摘要

Generation of constitutively active androgen-receptor (AR)-variant AR-V7, activation of glucocorticoid receptor (GR) signaling, and lineage switch from epithelial to neuroendocrine of prostate cancer (PCa) cells are three emerging mechanisms by which prostate tumor cells use to evade targeted therapy with androgen-receptor pathway inhibitors (ARPIs). There are no drugs or pipeline-agents that target these mechanisms in PCa therapeutics. Our previous and preliminary studies indicate that histone lysine demethylase KDM4B is associated with these mechanisms and may be a druggable target in castration-resistant prostate cancer (CRPC). KDM4B promotes the expression of cell cycle genes, AR-V7, and neuroendocrine markers. Genetic inactivation or pharmacological inhibition of KDM4B downregulates the expression of these genes and suppresses CRPC growth. We have generated proto-type KDM4B inhibitor B3 that effectively inhibited the growth of AR-negative and neuroendocrine-like PC3 xenograft in vivo. B3 also suppresses the growth of 22Rv1 tumor that expresses high levels of AR and AR-V7 in castrated mice and has synergistic effect with the GR antagonist CORT125134. To improve the selectivity and efficacy of B3, we performed multiple rounds of structure-based virtual screening, computational analyses, chemical synthesis, and primary cell-based screens. From >200 chemical compounds, we identified 3 more lead compounds that have improved IC50 on KDM-driven cell growth inhibition compared to that of B3. The synthesis of these chemical entities and their use in oncology have been filed for patent protection. Here we will test the efficacy of these lead compounds in various prostate xenograft models and characterize their ADME (Absorption, distribution, metabolism, and excretion) and pharmacokinetics-pharmacodynamics (PK/PD) properties with two specific aims. Aim 1. To establish the efficacy and enzymatic selectivity of candidate compound. We will test the efficacy of B3 and B3-analogs in xenografts derived from PCa models that have various degree of androgen responsiveness. We also include the non- prostate HeLa cells as a control and will perform RNA-seq to identify common and prostate cancer unique gene signature associated with the candidate compound. Selectivity of the candidate will be tested for its ability to inhibit specific KDM enzymatic activity in the demethylase assay. Aim 2. To establish the physiochemical and ADME properties of candidate compound. The drug-likeness of the candidate will be characterized including its physiochemical properties, in vitro metabolic stability, cell permeability, plasma protein binding, and PK/PD properties. The outcome of the proposal will provide us information to identify biomarker-defined subgroup(s) of PCa patients and to evaluate the effect of targeted therapy. The information will also guide us in designing and optimizing the drug-delivery route and drug formulation and performing PK/PD modeling in human in the phase II pre-IND studies. Milestone: We will prioritize the lead compounds based on their efficacy, selectivity, and ADME/PK/PD properties and take top one/two compound(s) on the list forward to phase II studies.

生成组成活性雄激素受体（AR）变异AR- v7，激活糖皮质激素受体