- 著者
- Katsuhiko Sekimata Tomohiro Sato Naoki Sakai
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.68, no.3, pp.194-200, 2020-03-01 (Released:2020-03-01)
- 参考文献数
- 70
- 被引用文献数
- 8
Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.
- 著者
- Tomohiro SATO Yuichi HIDAKA Shunichi KAMIMURA
- 出版者
- JAPANESE SOCIETY OF VETERINARY SCIENCE
- 雑誌
- Journal of Veterinary Medical Science (ISSN:09167250)
- 巻号頁・発行日
- vol.72, no.1, pp.29-33, 2010 (Released:2010-02-04)
- 参考文献数
- 15
- 被引用文献数
- 5 6
The growth effect of sugar supplementation was determined in 49 retarded growth calves. Calves were supplemented with sugar at 1 g/kg BW 2 times weekly for 8 weeks. Glucose tolerance tests prior to the experiment showed no difference between the retarded growth calves and normal growth controls. After sugar supplementation, the calves were classified into 4 groups characterized by high (H) or low (L) periodic changes in daily weight gain (DG) with a breakpoint of 0.8 kg/d in three periods, birth to sugar supplementation (Birth-Pre), the 8 weeks during supplementation (Pre-Post) and after feeding to delivery to market (Post-Market). The periodic DG showed a marked increase after supplementation in Pre-Post and Post-Market compared with before supplementation during Birth-Pre in 2 groups (0.93 and 1.11 vs. 0.51 kg/day for L-H-H [n=19], 0.66 and 1.19 vs. 0.42 kg/day for L-L-H [n=24]), but no difference was observed in L-H-L (n=3) and L-L-L (n=3). Peripheral blood was collected on the day before supplementation (Pre), 8 weeks after supplementation (Post) and eight weeks after cease of supplementation. The blood concentrations of both insulin-like growth factor-1 (IGF-1) and glucose showed significant increases in L-H-H and L-L-H, but decreases in non-esterified fatty acid were observed in L-H-H and L-L-L on day Post compared with day Pre, respectively (p<0.05). At delivery to market, the sugar-supplemented calves had body weights similar to the market average. The growth effect of sugar supplementation could be stimulated through rumen papillae development induce by sucrose, the main component of table sugar.
- 著者
- Katsuhiko Sekimata Tomohiro Sato Naoki Sakai Hisami Watanabe Chiemi Mishima-Tsumagari Tomonori Taguri Takehisa Matsumoto Yoshifumi Fujii Noriko Handa Teruki Honma Akiko Tanaka Mikako Shirouzu Shigeyuki Yokoyama Kohei Miyazono Yoshinobu Hashizume Hiroo Koyama
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.67, no.3, pp.224-235, 2019-03-01 (Released:2019-03-01)
- 参考文献数
- 17
- 被引用文献数
- 11
Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure–activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.