Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation

Abstract

The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC50 ∼ 5 nM). Moreover, kinase profiling and cell-line profiling revealed BPR1K871 to be a potential multi-kinase inhibitor. Functional studies using western blot and DNA content analysis in MV4-11 and HCT-116 cell lines revealed FLT3 and AURKA/B target modulation inside the cells. In vivo efficacy in AML xenograft models (MOLM-13 and MV4-11), as well as in solid tumor models (COLO205 and Mia-PaCa2), led to the selection of BPR1K871 as a preclinical development candidate for anti-cancer therapy. Further detailed studies could help to investigate the full potential of BPR1K871 as a multi-kinase inhibitor.

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

“…A Varian Mercury-400 spectrometer was used to record 1 H NMR spectra and an Agilent MSD-1100 ESI-MS/MS system was used to record low-resolution mass spectra (LRMS). Purity of the synthesized compounds was determined with an Hitachi 2000 series HPLC system using C-18 column (Agilent ZORBAX Eclipse XDB-C18 5 μm, 4.6 mm × 150 mm) 78 .…”

Colloidal Assemblies Composed of Polymeric Micellar/Emulsified Systems Integrate Cancer Therapy Combining a Tumor-Associated Antigen Vaccine and Chemotherapeutic Regimens

“…In a previous study, DBPR114 was proven to be a potent multi-kinase inhibitor for the treatment of AML [ 7 ]. In this study, the anti-proliferative activity of DBPR114 was determined to inhibit proliferation against MOLM-13, an FLT3-ITD mutation-positive AML cell line [ 7 ].…”

“…In a previous study, DBPR114 was proven to be a potent multi-kinase inhibitor for the treatment of AML [ 7 ]. In this study, the anti-proliferative activity of DBPR114 was determined to inhibit proliferation against MOLM-13, an FLT3-ITD mutation-positive AML cell line [ 7 ]. As shown in Table 2 , a formulation of DBPR114/DMSO could induce high-level anti-proliferative activity in MOLM-13; however, replacing the DMSO solvent with water attenuated DBPR114 activity in vitro.…”

“…Interestingly, additional supplementation of DBPR114 micelles was able to further slow tumor growth within 21 days; beyond, the incorporation of DBPR114 cannot give enough tumor regression in thymoma EG7 cell line. It should be noted that a single treatment of DBPR114 is a multi-kinase inhibitor targeted for AML cell line through the FLT3 pathway, and the low-level anti-proliferative activity was detected in an FLT3-negative leukemia cell line [ 7 ]. Here, we demonstrated that DBPR114 could play an auxiliary role in the expansion of antitumor activity intrinsic to tumor-associated antigen therapy.…”

“…The objective of this study was to combine two therapeutic processes, a tumor-associated antigen vaccine and chemotherapeutic regimens, effectively reinforcing each other via co-delivery of antitumor drug/antigen agents to integrate the efficacy of cancer therapy ( Figure 1 ). First, we conducted a comprehensive analysis to determine the effects of a polymeric micellar delivery system on the disposition of the poorly water-soluble drug DBPR114, a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) currently formulated in a co-solvent system consisting of DMSO/cremophor EL/saline (10/20/70) prior to intravenous administration [ 7 ]. AB-type diblock copolymers made of poly(ethylene glycol)–polylactide (PEG–PLA) were synthesized by ring-opening polymerization of lactide onto the hydroxyl end of methoxy poly(ethylene glycol) (MePEG) [ 4 ].…”