University of Sussex
haematol.2019.238584.full.pdf (2.43 MB)

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-?B activity and synergise with bortezomib and ibrutinib in hematological cancers

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posted on 2023-06-07, 06:59 authored by Thomas Lewis, David B Corcoran, David E Thurston, Peter J Giles, Kevin Ashelford, Elisabeth J Walsby, Christopher D Fegan, Andrea PepperAndrea Pepper, Khondaker Miraz Rahman, Christopher PepperChristopher Pepper
Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-?B activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-?B with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-?B DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-?B subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-?B regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-?B plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-?B-driven cancers, particularly in the context of relapsed/refractory disease.


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