SBIR Phase I: Cell-penetrating monobodies targeting oncogenic KRAS

SBIR 第一阶段：针对致癌 KRAS 的细胞穿透单体

• 批准号: 2321926
• 负责人: Johnathan Rabb
• 金额: $ 27.5万
• 依托单位: COVALABIO INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321926&HistoricalAwards=false
• 关键词: SBIR; Phase; Cell; penetrating; monobodies

The broader impact of this Small Business Innovation Research (SBIR) Phase I project lies in technological development of a new pharmaceutical intervention called cell-penetrating monobodies (CPM). The validation of this new CPM intervention will be demonstrated by designing potent and selective CPM-based inhibitors targeting certain cancers. The success of this project will establish a powerful pharmaceutical technology for designing personalized therapies to treat the oncogenic mutant-driven lung, pancreatic, and colorectal cancers, where treatment options are extremely limited. This project will also enhance the academia-industry partnership, strengthen a burgeoning life science ecosystem in the Buffalo area, and develop a globally competitive STEM workforce for the Western New York region.The proposed project addresses a critical barrier in the clinical translation of monobodies - a class of powerful tool biologics that are not cell-permeable despite their small size. The CPM technology overcomes this barrier by combining orthogonal crosslinking  a proprietary method to rigidify monobody structure through site-specific inter-strand crosslinking - with monobody surface supercharging. As a result, the CPM technology potentially possesses several innovative features: 1) genetic modifications facilitate recombinant production of CPM in bacteria both at research scale and for manufacturing; 2) high binding affinity and specificity toward intracellular oncogene targets can be readily obtained using well-established display technologies; and 3) robust cytosolic transport efficiency can be obtained owing to the rigid scaffold and tunable surface charge. This project aims to unlock the commercial value of CPM technology by identifying potent and selective inhibitors oncogenic KRAS mutants that proved to be elusive with the small-molecule approach. Extensive optimizations of charge distribution and physicochemical properties will be performed using a reported monobody-based KRAS inhibitor as a template, with a goal to identify one CPM with sub-micromolar inhibitory activity in the KRAS mutant-harboring cell lines.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项小型企业创新研究（SBIR）I阶段项目的更广泛影响在于技术开发的新药干预措施，称为细胞 - 渗透单体形成（CPM）。通过设计针对某些癌症的潜在和选择性的基于CPM的抑制剂，将证明这种新CPM干预的验证。该项目的成功将建立一种强大的药物技术，用于设计个性化疗法，以治疗致癌突变型肺，胰腺和有色癌症，在治疗方案非常有限。 This project will also enhance the academia-industry partnership, strengthening a brurgeoning life science ecosystem in the Buffalo area, and develop a globally competitive STEM workforce for the Western New York region.The proposed project addresses a critical barrier in the clinical translation of monobodies - a class of powerful tool biologics that are not cell-permeable mission their small size. CPM技术通过将正交交联的方法结合一种专有方法，通过特定于位点特异性的跨链接交联 - 与单体表面的增压来克服这一障碍。结果，CPM技术可能会潜在一些创新的特征：1）遗传修饰有助于在研究量表和制造范围内促进细菌中CPM的重组产生； 2）使用公认的显示技术可以轻松获得对细胞内癌基靶标的高结合亲和力和特异性； 3）由于刚性支架和可调的表面电荷，可以获得鲁棒的胞质运输效率。该项目旨在通过识别潜在的和选择性抑制剂的致癌KRAS突变体来释放CPM技术的商业价值，而这些潜在和选择性抑制剂通过小分子的方法被证明是难以捉摸的。 Extensive optimizations of charge distribution and physical properties will be performed using a reported monobody-based KRAS inhibitor as a template, with a goal to identify one CPM with sub-micromolar inhibitory activity in the KRAS mutant-harboring cell lines.This award reflects NSF's statutory mission and has been deemed precious of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.