Background:

AMG 319, a highly selective inhibitor of phosphoinositide 3-kinase p110δ isoform (PI3Kδ) [1], with an IC50 value less than 10 nM [2].

PI3Kδ plays an essential role in B-cell receptor (BCR) signaling. PI3Kδ is expressed in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) [1].

C-Akt, a serine-threonine kinase is one target of PI39K. C-Akt is the prototypical member of a mammalian Akt isoform family. The regulation to Akt may be phosphorylation or direct binding the Akt pleckstrin homology domain with PI39K lipid products. PI39K-independent Akt stimuli had been identified [3]. AMG 319 inhibited basal AKT phosphorylation and proliferation in lymphoid tumor cells [1].

28 patients received AMG 319. In a CLL patient after 1 dose of AMG 319, grade 3 hemolytic anemia at 25 mg was produced. All CLL samples with an inducible signal (60%) showed coverage of BCR-induced pAKT (ex-vivo IgD stimulated) dose-dependently; at 400 mg, near complete inhibition was seen for 24 hours. Baseline % of T-regulatory cells was elevated in CLL patients (14.4% ± 7.6%). But during treatment (14/19 patients), the elevated T regulatory cells tended to normalize. This suggested that the drug might produce immune restoration. By physical exam, all 20 evaluable patients showed greater than 50% lymph node (LN) reduction, 15 (75%) patients showed greater than 90% LN reduction. This response was present in all cytogenetic subtypes [1].

参考文献:
[1].  Glenn M, Mato AR, Allgood SD, et al. First-in-human study of AMG 319, a highly selective, small molecule inhibitor of PI3Kδ, in adult patients with relapsed or refractory lymphoid malignancies. Blood, 2013, 122(21): 678-678.
[2].  Brana I, Siu LL. Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment. BMC medicine, 2012, 10(1): 1.
[3].  Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997, 91(2): 231-241.