Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Abstract

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

Dasatinib suppression of medulloblastoma survival and migration is markedly enhanced by combining treatment with the aurora kinase inhibitor AT9283

“…The combination of Src and Aurk inhibition synergistically inhibits ovarian and colorectal cell growth in vitro [38–40], as well as leukemia and solid tumor growth in vivo [38, 40]. However, our study is the first to demonstrate the efficacy of this molecularly targeted combination for MB, and to our knowledge, is the first preclinical investigation of the specific combination of dasatinb and AT9283.…”

Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies

“…Ilorasertib is a novel ATP-competitive multitargeted kinase inhibitor of Aurora kinases (A, B, C), as well as all known members of the VEGF/PDGF and Src families of tyrosine kinases (20). …”

“…After oral administration, the C max , AUC, and t 1/2 of ilorasertib were generally dose proportional, although there was a higher variability at low doses. Dividing the weekly dose into 2 doses given 23 hours apart led to a lower C max and prolonged the plasma exposure above the lower threshold of the preclinical efficacious concentration of 500 ng/mL (20). This dosing schedule was based on and aligned with the preclinical studies of ilorasertib.…”

“…Ilorasertib is a novel ATP-competitive multitargeted kinase inhibitor of Aurora kinases (A, B, C), as well as all known members of the VEGF/PDGF and Src families of tyrosine kinases (20). Because ilorasertib targets multiple pathways of tumor progression, it may have the potential to overcome the limitations of the more selective kinase inhibitors.…”

“…Because ilorasertib targets multiple pathways of tumor progression, it may have the potential to overcome the limitations of the more selective kinase inhibitors. Preclinical antitumor activity included tumor regression and prolonged survival in multiple xenograft models of lymphoma, acute leukemias, and MDS, as well as in solid tumors (19,20). The primary objectives of this phase 1 dose-escalation trial were to determine the safety and pharmacokinetic profiles of ilorasertib in patients with hematologic malignancies.…”