PIK-75 HCl

PIK-75是PI3K亚型p110α的抑制剂，IC50值为5.8 nM[1]。

在急性髓性白血病细胞中，PIK-75靶向PI3K的 p110α亚型，导致Bcl-xL与Bak之间连接丧失。PIK-75也能短暂减少Cdk7/9，导致Mcl-1蛋白减少，并减轻其对促凋亡Bak的抑制。Bcl-xL与Mcl-1的同时缺失导致快速的细胞凋亡。[2]在人单核细胞-内皮细胞中，PIK-75可抑制下游信号事件，包括AKT磷酸化、IKK活化和NF-kB转录。PIK-75可抑制体外和体内的TNF-α和IL-6生成，减少E-selectin、ICAM-1和VCAM-1表达，并阻断细胞粘附[3]。在人类平滑肌细胞中，PIK-75减少TNF-α诱导的CD38在哮喘和非哮喘细胞中的表达[4]。在胰腺β细胞中，PIK-75急性治疗增加葡萄糖诱导的胰岛素分泌[5]。

在体内，PIK-75显著抑制与葡聚糖硫酸钠诱发的小鼠结肠炎相关的组织学畸形。PIK-75在结肠中可减弱实验性炎症[3]。

参考文献：
[1].  Zheng Z, Amran SI, Thompson PE, Jennings IG. Isoform-selective inhibition of phosphoinositide 3-kinase: identification of a new region of nonconserved amino acids critical for p110α inhibition. Mol Pharmacol. 2011 Oct;80(4):657-64.
[2].  Thomas D, Powell JA, Vergez F, Segal DH, Nguyen NY, Baker A, Teh TC, Barry EF, Sarry JE, Lee EM, Nero TL, Jabbour AM, Pomilio G, Green BD, Manenti S, Glaser SP, Parker MW, Lopez AF, Ekert PG, Lock RB, Huang DC, Nilsson SK, Récher C, Wei AH, Guthridge MA. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013 Aug 1;122(5):738-48.
[3].  Dagia NM, Agarwal G, Kamath DV, Chetrapal-Kunwar A, Gupte RD, Jadhav MG, Dadarkar SS, Trivedi J, Kulkarni-Almeida AA, Kharas F, Fonseca LC, Kumar S, Bhonde MR. A preferential p110alpha/gamma PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-kappaB-dependent manner. Am J Physiol Cell Physiol. 2010 Apr;298(4):C929-41.
[4].  Jude JA, Tirumurugaan KG, Kang BN, Panettieri RA, Walseth TF, Kannan MS. Regulation of CD38 expression in human airway smooth muscle cells: role of class I phosphatidylinositol 3 kinases. Am J Respir Cell Mol Biol. 2012 Oct;47(4):427-35.
[5].  Aoyagi K, Ohara-Imaizumi M, Nishiwaki C, Nakamichi Y, Ueki K, Kadowaki T, Nagamatsu S. Acute inhibition of PI3K-PDK1-Akt pathway potentiates insulin secretion through upregulation of newcomer granule fusions in pancreatic β-cells. PLoS One. 2012;7(10):e47381.