PIK-75 is a specific inhibitor of p110α isoform of PI3K with IC50 of 5.8 nM [1].
In acute myeloid leukemia cells, PIK-75 targeted the p110α isoform of PI3K, which led to a loss of connection between Bcl-xL and Bak. PIK-75 also transiently decreased Cdk7/9, leading to loss of Mcl-1 protein, and alleviation of its inhibition of pro-apoptotic Bak. The simultaneous loss of Bcl-xL and Mcl-1 led to rapid apoptosis. [2] In human monocyte-endothelial cell, PIK-75 suppressed the events of downstream signaling, including AKT phosphorylation, IKK activation, and NF-kB transcription. PIK-75 inhibited in vitro and in vivo production of TNF-α and IL-6, decreased the E-selectin, ICAM-1, and VCAM-1 expression, and blocked cell adhesion [3]. In human smooth muscle cells, PIK-75 decreased TNF-α-induced CD38 expression in asthmatic and nonasthmatic cells [4]. In pancreatic β-cells, acute treatment with PIK-75 enhanced the glucose-induced insulin secretion [5].
In vivo, PIK-75 significantly suppressed the histological abnormalities associated with dextran sulfate sodium-induced murine colitis. PIK-75 can attenuate experimental inflammation in the colon [3].
References:
[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.
