Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor.
BACKGROUND
Based on in vitro and animal data, PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear.


OBJECTIVE
To strengthen the PI3Kβ target validation using the novel, short-acting inhibitor AZD6482.


RESULTS
AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC(50) 0.01 μm). A maximal anti-platelet effect was achieved at 1 μm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC(50) of 4.4 μm). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 μm but reduced by about 60% at a plasma exposure of 27 μm. In man, the homeostasis model analysis (HOMA) index increased by about 10-20% at the highest plasma concentration of 5.3 μm.


CONCLUSIONS
This is the first human target validation for PI3Kβ inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at 'supratherapeutic' plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition.
Department of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden. sven.nylander@astrazeneca.com
S
S
Nylander
B
B
Kull
J A
JA
Björkman
J C
JC
Ulvinge
N
N
Oakes
B M
BM
Emanuelsson
M
M
Andersson
T
T
Skärby
T
T
Inghardt
O
O
Fjellström
D
D
Gustafsson
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000293:Adolescent; D000328:Adult; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D006490:Hemostatics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010979:Platelet Function Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control; D013997:Time Factors; D055815:Young Adult; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
C578518:2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid; D005343:Fibrinolytic Agents; D006490:Hemostatics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D062367:ortho-Aminobenzoates; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose