molecules of the month

Context. DNL201 (Denali Therapeutics) is an oral, CNS-penetrating, ATP-competitive leucine-rich repeat kinase 2 (LRRK2) inhibitor being developed for Parkinson’s disease (PD). PD remains incurable; current treatment options only alleviate disease symptoms and do not prevent progression. Due to its well known involvement in familial and even sporadic/idiopathic PD, LRRK2, particularly the G2019S variant, has been a hotly pursued target in the last decade, with at least a dozen promising agents having been reported (e.g., Merck’s MLi-2 and “compound 24” which we have previously featured). However, clinical advancement of these molecules has been hampered by concerns about potential lung toxicity. Although a previous preclinical study evaluating pulmonary toxicity in macaques seemed to validate these concerns, data provided by Denali scientists in…