Leucine rich repeat kinase 2 (LRRK2) inhibitors based on indolinone scaffold: Potential pro-neurogenic agents Articles uri icon

authors

  • SALADO, IRENE G.
  • ZALDIVAR DIEZ DE BONILLA, JOSEFA
  • SEBASTIÁN-PÉREZ, VÍCTOR
  • LI, LINGLING
  • GEIGER, LARISSA
  • GONZÁLEZ, SILVIA
  • GONZALEZ GASPAR, SARA
  • CAMPILLO, NURIA E.
  • GIL, CARMEN
  • MORALES, AIXA V.
  • PÉREZ, DANIEL I.
  • MARTÍNEZ, ANA
  • MARTINEZ FINKELSHTEIN, ANDREI

publication date

  • September 2017

start page

  • 328

end page

  • 342

volume

  • 138

International Standard Serial Number (ISSN)

  • 0223-5234

Electronic International Standard Serial Number (EISSN)

  • 1768-3254

abstract

  • Leucine-rich repeat kinase 2 (LRRK2) is one of the most pursued targets for Parkinson's disease (PD) therapy. Moreover, it has recently described its role in regulating Wnt signaling and thus, it may be involved in adult neurogenesis. This new hypothesis could give rise to double disease-modifying agents firstly by the benefits of inhibiting LRRK2 and secondly by promoting adult neurogenesis. Herein we report, the design, synthesis, biological evaluation, SAR and potential binding mode of indoline-like LRRK2 inhibitors and their preliminary neurogenic effect in neural precursor cells isolated from adult mice ventricular-subventricular zone. These results open new therapeutic horizons for the use of LRRK2 inhibitors as neuroregenerative agents. Moreover, the indolinone derivatives here prepared, inhibitors of the kinase activity of LRRK2, may be considered as pharmacological probes to study the potential neuroregeneration of the damaged brain.

subjects

  • Biology and Biomedicine
  • Medicine
  • Pharmacy
  • Psychology

keywords

  • lrrk2 inhibitors; protein kinase inhibitors; indolinone; adult neurogenesis; neural stem cell; regenerative medicine