Biological Activity
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].
References
[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.
