ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme.
Glioblastoma multiforme is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with glioblastoma multiforme beyond 14 to 15 months, in part because the blood-brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as glioblastoma multiforme treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests glioblastoma multiforme cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood-brain barrier. Further investigation in a syngeneic orthotopic mouse model of glioblastoma multiforme shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. Mol Cancer Ther; 15(9); 2018-29. ©2016 AACR.
Department of Pharmacology, University of Washington, Seattle, Washington.
Allison E
AE
Cherry
Department of Pharmacology, University of Washington, Seattle, Washington.
Brian R
BR
Haas
Department of Pharmacology, University of Washington, Seattle, Washington. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington.
Alipi V
AV
Naydenov
Department of Pharmacology, University of Washington, Seattle, Washington. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington.
Susan
S
Fung
Department of Pharmacology, University of Washington, Seattle, Washington.
Cong
C
Xu
Department of Pharmacology, University of Washington, Seattle, Washington.
Katie
K
Swinney
Department of Physiology and Biophysics, University of Washington, Seattle, Washington.
Michael
M
Wagenbach
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Jennifer
J
Freeling
Department of Pharmacology, University of Washington, Seattle, Washington. Howard Hughes Medical Institute, University of Washington, Seattle, Washington.
David A
DA
Canton
Department of Pharmacology, University of Washington, Seattle, Washington.
Jonathan
J
Coy
Department of Pharmacology, University of Washington, Seattle, Washington.
Eric A
EA
Horne
Department of Comparative Medicine, University of Washington, Seattle, Washington.
Barry
B
Rickman
Department of Physiology and Biophysics, University of Washington, Seattle, Washington.
Juan Jesus
JJ
Vicente
Department of Pharmacology, University of Washington, Seattle, Washington. Howard Hughes Medical Institute, University of Washington, Seattle, Washington.
John D
JD
Scott
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Rodney J Y
RJ
Ho
Department of Comparative Medicine, University of Washington, Seattle, Washington.
Denny
D
Liggitt
Department of Physiology and Biophysics, University of Washington, Seattle, Washington.
Linda
L
Wordeman
Department of Pharmacology, University of Washington, Seattle, Washington. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. nstella@uw.edu.
Nephi
N
Stella
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D053758:Nanoparticles; D010865:Pilot Projects; D012995:Solubility; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D053148:Caspase 3