Hoshikawa Tamaki, Watanabe Toru, Kotake Makoto, Tiberghien Nathalie, Woo Chi-Kit, Lewis Sian, Briston Thomas, Koglin Mumta, Staddon James M, Powney Ben, Schapira Anthony H V, Takle Andrew K
Hatfield Research Laboratories, Eisai Ltd., Hatfield AL10 9SN, United Kingdom.
Hatfield Research Laboratories, Eisai Ltd., Hatfield AL10 9SN, United Kingdom.
Bioorg Med Chem Lett. 2023 Feb 1;81:129130. doi: 10.1016/j.bmcl.2023.129130. Epub 2023 Jan 12.
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene, loss of function variants of which cause an autosomal recessive lysosomal storage disorder, Gaucher disease (GD). Heterozygous variants of GBA1 are also known as the strongest common genetic risk factor for Parkinson's disease (PD). Restoration of GCase enzymatic function using a pharmacological chaperone strategy is considered a promising therapeutic approach for PD and GD. We identified compound 4 as a GCase pharmacological chaperone with sub-micromolar activity from a high-throughput screening (HTS) campaign. Compound 4 was further optimised to ER-001230194 (compound 25). ER-001230194 shows improved ADME and physicochemical properties and therefore represents a novel pharmacological chaperone with which to investigate GCase pharmacology further.
葡萄糖脑苷脂酶（GCase）是一种由GBA1基因编码的溶酶体酶，该基因的功能缺失变体可导致常染色体隐性溶酶体贮积症——戈谢病（GD）。GBA1的杂合变体也是帕金森病（PD）最强的常见遗传风险因素。采用药理学伴侣策略恢复GCase酶功能被认为是治疗PD和GD的一种有前景的方法。我们通过高通量筛选（HTS）活动，从化合物中鉴定出化合物4作为一种具有亚微摩尔活性的GCase药理学伴侣。化合物4进一步优化为ER-001230194（化合物25）。ER-001230194显示出改善的吸收、分布、代谢和排泄（ADME）及物理化学性质，因此代表了一种新型药理学伴侣，可用于进一步研究GCase药理学。
