DNL201

DNL201 is an investigational, orally available, brain-penetrant, selective small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2). It acts as an ATP-competitive inhibitor and is designed to reduce LRRK2 kinase activity. LRRK2 mutations are the most common genetic risk factors for Parkinson's disease; increased LRRK2 activity impairs lysosomal function and may contribute to disease pathogenesis. By inhibiting LRRK2, DNL201 aims to restore lysosomal function and potentially modify the course of Parkinson’s disease. Preclinical studies demonstrated that DNL201 reduces phosphorylation of both LRRK2 at serine-935 (pS935) and its substrate Rab10 at threonine-73 (pT73), with improved lysosomal function observed in cellular models. In phase 1 clinical trials involving healthy volunteers and patients with Parkinson’s disease, DNL201 showed robust CNS penetration, significant target engagement, was generally well tolerated at active doses, and altered downstream biomarkers related to lysosomal health. Denali Therapeutics developed DNL201 primarily for Parkinson’s disease; however, development was deprioritized in favor of a follow-up compound (DNL151), with DNL201 now serving as a backup[1][3][6].

Other names

n2-(3-(2-(2h-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1h-pyrazol-5-yl)-n4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine