生物活性

• 描述Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase that synthesizes two phosphoinositides (PIs), regulating degradative and recycling endosomal trafficking, cytoskeletal rearrangement and autophagy. Apilimod Mesylate is a mesylate form of Apilimod. Apilimod is a 1,3,5-triazine derivative that binds to and inhibits PIKfyve kinase activity with an IC50 value of 14 nM. Treatment of apilimod (10 nM and 1 μM) for 120min decreased PI(3,5)P₂ in HeLa cells at a dose-dependent manner. RAW264.7 cells treated with 10 nM Apilimod for 3h showed enlarged vacuoles due to the disruption of PIKfyve activity. In A549 cells, overexpression of wild-type PIKfyve resulted in the disappearance of vacuoles induced by 10 nM apilimod. Bone-marrow-derived dendritic cells from mutant mice demonstrated extensive vacuole formation with the treatment of 1 μM apilimod^[3]. Apilimod showed selective antiproliferative activity in B-NHL cells with an IC50 value of 142 nM. After the treatment of 200 nM apilimod for 3 days, increased apoptosis was shown in SU-DHL-10 B-NHL cells. In a subcutaneous daudi burkitt lymphoma xenograft model, apilimod (50 - 150 mg/kg free base; p.o., once a day) displayed tumor growth inhibition at a dose-dependent manner. The growth inhibition was also observed in SU-DHL-6 DLBCL model treated with both apilimod (41 mg/kg free base, p.o., twice a day) and rituximab (7 mg/kg, i.p.)^[4].
• 作用机制Apilimod is a potent, highly selective PIKfyve inhibitor that binds to the PIKfyve domain (amino acids 1522 to 2098) to block the phosphotransferase activity of PIKfyve, thereby inhibiting IL-12/23p40^[3].

• 动物研究
  剂量	C57BL/6J Mice: 5 mg/kg, 20 mg/kg[3] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00642629	Active, Moderate to Severe Rhe... more >>umatoid Arthritis Collapse <<	Phase 2	Completed	-	Netherlands ... more >> Academic Medical Center Amsterdam, Netherlands Collapse <<
  NCT00263237	Common Variable Immunodeficien... more >>cy Collapse <<	Phase 1	Completed	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<
  NCT00088062	Crohn's Disease	Phase 1 Phase 2	Completed	-	United States, Arizona ... more >> Advanced Clinical Therapeutics Tucson, Arizona, United States, 85712 United States, California Advanced Clinical Research Institute Anaheim, California, United States, 92801 United States, Florida Venture Research Institute, LLC North Miami Beach, Florida, United States, 33162 Shafran Gastoenterology Center Winter Park, Florida, United States, 32789 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 University of Chicago Chicago, Illinois, United States, 60637 United States, Kansas Heart of America Research Institute Topeka, Kansas, United States, 66614 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States, 02114 Boston Medical Center Boston, Massachusetts, United States, 02118 Brigham and Women's Hospital Boston, Massachusetts, United States, 02215 United States, New York Long Island Clinical Research Great Neck, New York, United States, 10021 Rochester Institute for Digestive Diseases and Sciences, Inc Rochester, New York, United States, 14607 United States, North Carolina Carolina Research Associates Charlotte, North Carolina, United States, 28262 Wake Research Associates Raleigh, North Carolina, United States, 27612 United States, Oregon West Hills GI Portland, Oregon, United States United States, Pennsylvania Blair Gastroenterology Associates Altoona, Pennsylvania, United States, 16602 United States, Tennessee Memphis Gastroenterology Group Memphis, Tennessee, United States, 38120 Nashville Medical Research Institute Nashville, Tennessee, United States, 37205 Collapse <<

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• 参考文献

• [1] Gayle S, Landrette S, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768-1778.

  [2] Wada Y, Lu R, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood. 2007;109(3):1156-64

  [3] Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, Billich A, Zhang B, Feng Y, Klumpp M, Rondeau JM, Fazal AN, Wilson CJ, Myer V, Joberty G, Bouwmeester T, Labow MA, Finan PM, Porter JA, Ploegh HL, Baird D, De Camilli P, Tallarico JA, Huang Q. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013 Jul 25;20(7):912-21.

  [4] Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T, Rothberg J, Lichenstein H. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768-1778.