Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening.
Inclusions comprised of fibrils of the microtubule- (MT-) associated protein tau are found in the brains of those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published, but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of approximately 292000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavin T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZs). A number of ATPZ analogues were synthesized, and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Abeta(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.
Crowe
Alex
A
Center for Neurodegenerative Disease Research, Institute on Aging, and Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Huang
Wenwei
W
Ballatore
Carlo
C
Johnson
Ronald L
RL
Hogan
Anne-Marie L
AM
Huang
Ruili
R
Wichterman
Jennifer
J
McCoy
Joshua
J
Huryn
Donna
D
Auld
Douglas S
DS
Smith
Amos B
AB
Inglese
James
J
Trojanowski
John Q
JQ
Austin
Christopher P
CP
Brunden
Kurt R
KR
Lee
Virginia M-Y
VM
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D055503:Protein Multimerization; D011724:Pyridazines / Q000737:chemistry*; D024801:Tauopathies / Q000473:pathology; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D011724:Pyridazines; D016875:tau Proteins