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Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for Wnt-driven breast cancer

开发细胞穿透性 β-连环蛋白拮抗剂肽作为 Wnt 驱动乳腺癌的候选治疗药物

基本信息

批准号：
10324076
负责人：
Jim Rotolo
金额：
$ 40.93万
依托单位：
SAPIENCE THERAPEUTICS, INC.
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：
2021-09-02 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324076
关键词：
Adverse effects Affinity Amino Acid Sequence Amino Acid Substitution Amino Acids BCL9 gene Binding Binding Sites Biological Markers Cancer Etiology Cancer Patient Cancerous Cell Death Cell Line Cell Proliferation Cell Survival Cells Clinical Development Dose Drug Targeting Elements Gene Expression Genes Human In Vitro Literature Location Malignant Neoplasms Mediating Metastatic Neoplasm to Lymph Nodes Mus Neoplasm Metastasis Oncogenic Pathologic Pathway interactions Peptides Pharmaceutical Preparations Phase Phosphorylation Predisposition Prognosis Proteolysis Regimen Reporter Research Research Design Safety Signal Transduction Site Small Business Innovation Research Grant Specificity Structure-Activity Relationship Surrogate Markers TCF7L2 gene Testing Therapeutic Toxic effect Transactivation Transcription Coactivator angiogenesis antitumor effect base beta catenin cancer cell cancer initiation cancer subtypes cancer therapy chemical stability clinical efficacy commercialization cost cytotoxicity design enantiomer experimental study improved in vitro activity in vivo inhibitor/antagonist innovation lead candidate malignant breast neoplasm migration mouse model neoplastic cell new therapeutic target pharmacokinetics and pharmacodynamics preclinical evaluation programs receptor response side effect small molecule small molecule inhibitor targeted treatment therapeutic candidate tumor

项目摘要

ABSTRACT Dysregulation of Wnt/-catenin signaling is found in more than 20% of all cancers, including 50% of breast can- cers, and contributes to cancer initiation, angiogenesis, tumor migration and metastasis. However, attempts at developing a drug to inhibit -catenin have been thwarted by the inability of small molecule inhibitors to separate -catenin’s oncogenic from homeostatic functions, producing a toxic safety profile. BCL9 is a transcriptional co-activator that regulates oncogenic β-catenin-mediated gene transactivation. Disrup- tion of BCL9 interaction with β-catenin results in potent inhibition of -catenin-mediated oncogenic gene trans- activation without the GI toxicity associated with loss of signaling via APC or Axin. As BCL9 is highly expressed in tumors, but generally not normal cells, the β-catenin interaction with BCL9 represents an attractive, novel therapeutic target. Based on the above, we hypothesize that a peptide antagonist of β-catenin interaction with BCL9 will prove a safe and effective strategy for Wnt-driven cancers. Sapience has designed and synthesized a panel of β-catenin antagonist peptides (BCAPs) to disrupt the inter- action of β-catenin with BCL9, in which we introduced amino acid substitutions to the native BCL9 HD2 domain to enhance target affinity, included a non-toxic cell penetrating domain (CPD) for intracellular entry and D-amino acids to protect from proteolysis and confer chemical stability. Through structure-activity relationship (SAR)- based design, we developed a lead candidate, BCAP-58, with improved potency in vitro and in vivo. Through this SBIR program, we propose to develop an innovative inhibitor of -catenin/BCL9 interaction as a therapeutic for Wnt/-catenin-driven cancers, starting with breast cancer. We propose to characterize the in vitro (Specific Aim #1) and in vivo (Specific Aim #2) activity of BCAP-58. Initial experiments will evaluate the binding affinity of BCAP-58 with -catenin (Aim 1.1). Subsequently, the impact of BCAP-58 on Wnt/β-catenin activity will be determined by TOPFlash reporter, β-catenin phosphorylation and β-catenin subcellular localization (Aim 1.2). Finally, we will test the impact and target specificity of BCAP-58 on β-catenin-target gene expression by qPCR (Aim 1.3), and on cell proliferation and viability (Aim 1.4), against a panel of Wnt-dependent or -independent cell lines of various breast cancer subtypes and patient-derived tumoroids. To establish proof of concept for BCAP- 58 as a therapeutic for Wnt-dependent breast cancer, we will assess its repeat-dose toxicity and in vivo efficacy. First, we will establish a no adverse effect level (NOAEL) and PK profile in mice, to define the upper dosing limit (Aim 2.1). Next, we will investigate the dose-dependent activity of BCAP-58 in mouse models of the subtypes that demonstrate susceptibility to BCAP-58 in Aim 1 (Aim 2.2). Finally, we will characterize the impact of BCAP- 58 on β-catenin-mediated gene transactivation in vivo (Aim 2.3). Successful results will validate advancing BCAP-58 to IND-enabling preclinical evaluation, identify a maximally effective regimen and support a subsequent Phase II proposal, in support of an IND application.

摘要