Development of a 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitor as a novel anticancer agent with minimal toxicity

Abstract

BackgroundBoth the type I insulin-like growth factor receptor (IGF1R) and Src pathways are associated with the development and progression of numerous types of human cancer, and Src activation confers resistance to anti-IGF1R therapies. Hence, targeting both IGF1R and Src concurrently is one of the main challenges in combating resistance to the currently available anti-IGF1R-based anticancer therapies. However, the enhanced toxicity from this combinatorial treatment could be one of the main hurdles for this strategy, suggesting the necessity of developing a novel strategy for co-targeting IGF1R and Src to meet an urgent clinical need.MethodsWe synthesized a series of 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitors, selected LL28 as an active compound and evaluated its potential antitumor effects in vitro and in vivo using the MTT assay, colony formation assays, flow cytometric analysis, a tumor xenograft model, and the KrasG12D/+-driven spontaneous lung tumorigenesis model.ResultsLL28 markedly suppressed the activation of IGF1R and Src and significantly inhibited the viability of several NSCLC cell lines in vitro by inducing apoptosis. Administration of mice with LL28 significantly suppressed the growth of H1299 NSCLC xenograft tumors without overt toxicity and substantially reduced the multiplicity, volume, and load of lung tumors in the KrasG12D/+-driven lung tumorigenesis model.ConclusionsThe present results suggest the potential of LL28 as a novel anticancer drug candidate targeting both IGF1R and Src, providing a new avenue to efficient anticancer therapies. Further investigation is warranted in advanced preclinical and clinical settings.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0802-4) contains supplementary material, which is available to authorized users.

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

“…Body weight changes were monitored during the treatment. In vivo toxicity test was perform as described previously 66 . Briefly, blood was collected from euthanized mice by cardiac puncture.…”

Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src

“…Indeed, a combined inhibition of IGF-1R and the Src family kinases have been shown to enhance antitumor effects in various cancers by decreasing the activated survival pathways [34,35]. We have also shown that the dual inhibition of IGF-1R and Src could be a viable approach to develop effective anticancer therapies to overcome resistance [36].…”

“…The reduction of azides 4a-c, in the presence of triphenylphosphine, leads to the amine intermediates 5a-c, which were subsequently attached with thalidomide derivative 6 to obtain 7a-c, followed by a reduction with Fe/NH 4 Cl to provide 8a-c. PROTACs 10a-c were synthesized by coupling 8a-c with 2-chloro-4-arylamino-1,3-pyrimidines 9 in DMSO. The key intermediates 8a-b were also treated with their corresponding reagents 11a or 11b, to produce PROTACs 12a-d (Scheme 1) [36,47].…”

“…The reduction of azides 4a-c, in the presence of triphenylphosphine, leads to the amine intermediates 5a-c, which were subsequently attached with thalidomide derivative 6 to obtain 7a-c, followed by a reduction with Fe/NH4Cl to provide 8a-c. PROTACs 10a-c were synthesized by coupling 8a-c with 2-chloro-4-arylamino-1,3pyrimidines 9 in DMSO. The key intermediates 8a-b were also treated with their corresponding reagents 11a or 11b, to produce PROTACs 12a-d (Scheme 1) [36,47]. The thalidomide-attached linkers 8a-b were also coupled with azidoacetic acid 13 in the presence of EDC·HCl to provide 14a-b, which were further treated with N-substituted 4aminopyrazolo [3-d]pyrimidines intermediate (15) in the presence of copper sulfate and sodium ascorbate in THF/H2O/tBuOH to obtain the click products 16a-b via a copper (I)-catalyzed alkyne azide 1,3-dipolar cycloaddition (CuAAC) reaction (Scheme 2).…”

“…8a-b reacted with the bromopropyl group-attached pyrazolo [3 ,4-d]pyrimidin-4-amine (17) under the basic condition yielded PROTACs 18a-b. Next, N-propagylation of 8a-b under the basic condition afforded 20a-b, which were coupled with azido intermediate (19) via the CuAAC reaction to obtain the desired triazole products 21a-b [36].…”