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Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer
ACS Omega ( IF 3.7 ) Pub Date : 2024-02-28 , DOI: 10.1021/acsomega.3c09607 Ana C Puhl 1 , Renuka Raman 1 , Tammy M Havener 2 , Eni Minerali 1 , Anthony J Hickey 2, 3 , Sean Ekins 1
ACS Omega ( IF 3.7 ) Pub Date : 2024-02-28 , DOI: 10.1021/acsomega.3c09607 Ana C Puhl 1 , Renuka Raman 1 , Tammy M Havener 2 , Eni Minerali 1 , Anthony J Hickey 2, 3 , Sean Ekins 1
Affiliation
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Palmitoyl-protein thioesterase 1 (PPT1) is an understudied enzyme that is gaining attention due to its role in the depalmitoylation of several proteins involved in neurodegenerative diseases and cancer. PPT1 is overexpressed in several cancers, specifically cholangiocarcinoma and esophageal cancers. Inhibitors of PPT1 lead to cell death and have been shown to enhance the killing of tumor cells alongside known chemotherapeutics. PPT1 is hence a viable target for anticancer drug development. Furthermore, mutations in PPT1 cause a lysosomal storage disorder called infantile neuronal ceroid lipofuscinosis (CLN1 disease). Molecules that can inhibit, stabilize, or modulate the activity of this target are needed to address these diseases. We used PPT1 enzymatic assays to identify molecules that were subsequently tested by using differential scanning fluorimetry and microscale thermophoresis. Selected compounds were also tested in neuroblastoma cell lines. The resulting PPT1 screening data was used for building machine learning models to help select additional compounds for testing. We discovered two of the most potent PPT1 inhibitors reported to date, orlistat (IC50 178.8 nM) and palmostatin B (IC50 11.8 nM). When tested in HepG2 cells, it was found that these molecules had decreased activity, indicating that they were likely not penetrating the cells. The combination of in vitro enzymatic and biophysical assays enabled the identification of several molecules that can bind or inhibit PPT1 and may aid in the discovery of modulators or chaperones. The molecules identified could be used as a starting point for further optimization as treatments for other potential therapeutic applications outside CLN1 disease, such as cancer and neurological diseases.
中文翻译：
鉴定针对 CLN1 Batten 病和癌症的棕榈酰蛋白硫酯酶 1 的新调节剂和抑制剂
棕榈酰蛋白硫酯酶 1 (PPT1) 是一种尚未被研究的酶，由于其在与神经退行性疾病和癌症有关的几种蛋白质的去棕榈酰化中的作用而受到关注。 PPT1 在多种癌症中过度表达，特别是胆管癌和食道癌。 PPT1 抑制剂会导致细胞死亡，并且已被证明可以与已知的化疗药物一起增强对肿瘤细胞的杀伤作用。因此，PPT1 是抗癌药物开发的一个可行靶点。此外，PPT1 突变会导致溶酶体贮积症，称为婴儿神经元蜡样脂褐质沉着症（CLN1 病）。治疗这些疾病需要能够抑制、稳定或调节该靶点活性的分子。我们使用 PPT1 酶测定来鉴定分子，随后使用差示扫描荧光测定法和微尺度热泳进行测试。还在神经母细胞瘤细胞系中测试了选定的化合物。由此产生的 PPT1 筛选数据用于构建机器学习模型，以帮助选择其他化合物进行测试。我们发现了迄今为止报道的两种最有效的 PPT1 抑制剂：奥利司他 (IC 50 178.8 nM) 和棕榈抑素 B (IC 50 11.8 nM)。当在 HepG2 细胞中进行测试时，发现这些分子的活性降低，表明它们可能无法穿透细胞。体外酶学和生物物理测定的结合能够鉴定出几种可以结合或抑制 PPT1 的分子，并可能有助于发现调节剂或分子伴侣。 鉴定出的分子可以作为进一步优化的起点，作为 CLN1 疾病之外其他潜在治疗应用的治疗方法，例如癌症和神经系统疾病。
更新日期：2024-02-28
中文翻译：
鉴定针对 CLN1 Batten 病和癌症的棕榈酰蛋白硫酯酶 1 的新调节剂和抑制剂
棕榈酰蛋白硫酯酶 1 (PPT1) 是一种尚未被研究的酶，由于其在与神经退行性疾病和癌症有关的几种蛋白质的去棕榈酰化中的作用而受到关注。 PPT1 在多种癌症中过度表达，特别是胆管癌和食道癌。 PPT1 抑制剂会导致细胞死亡，并且已被证明可以与已知的化疗药物一起增强对肿瘤细胞的杀伤作用。因此，PPT1 是抗癌药物开发的一个可行靶点。此外，PPT1 突变会导致溶酶体贮积症，称为婴儿神经元蜡样脂褐质沉着症（CLN1 病）。治疗这些疾病需要能够抑制、稳定或调节该靶点活性的分子。我们使用 PPT1 酶测定来鉴定分子，随后使用差示扫描荧光测定法和微尺度热泳进行测试。还在神经母细胞瘤细胞系中测试了选定的化合物。由此产生的 PPT1 筛选数据用于构建机器学习模型，以帮助选择其他化合物进行测试。我们发现了迄今为止报道的两种最有效的 PPT1 抑制剂：奥利司他 (IC 50 178.8 nM) 和棕榈抑素 B (IC 50 11.8 nM)。当在 HepG2 细胞中进行测试时，发现这些分子的活性降低，表明它们可能无法穿透细胞。体外酶学和生物物理测定的结合能够鉴定出几种可以结合或抑制 PPT1 的分子，并可能有助于发现调节剂或分子伴侣。 鉴定出的分子可以作为进一步优化的起点，作为 CLN1 疾病之外其他潜在治疗应用的治疗方法，例如癌症和神经系统疾病。
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