Novel ALK5 inhibitor TP0427736 reduces TGF-β　induced growth inhibition in human outer root sheath cells and elongates anagen phase in mouse hair follicles.
BACKGROUND
Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}.


METHODS
For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-β-induced Smad2/3 phosphorylation in A549 cells and TGF-β-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation.


RESULTS
TP0427736 inhibited ALK5 kinase activity with an IC50of 2.72nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase.


CONCLUSIONS
TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA.　.
Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. Electronic address: ta-naruse@so.taisho.co.jp.
Takumi
T
Naruse
Pharmaceutical Affairs, Taisho Pharmaceutical Co., Ltd., Toshima-ku, Tokyo, Japan.
Mari
M
Aoki
Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Natsuko
N
Fujimoto
Department of Dermatology, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan.
Seiji
S
Arase
Department of Dermatology, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan.
Hajimu
H
Oura
Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Yasuji
Y
Ueda
Licensing & Business Development, Taisho Pharmaceutical Co., Ltd., Toshima-ku, Tokyo, Japan.
Akiko
A
Ikeda
D000287:Administration, Topical; D000505:Alopecia / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors; D004797:Enzyme-Linked Immunosorbent Assay; D018859:Hair Follicle / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C000624424:6-(4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl)-1,3-benzothiazole; D052160:Benzothiazoles; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
ALK5; Anagen phase; Androgenic alopecia; Smad2 phosphorylation; TGF-β