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

Lewis, Thomas, Corcoran, David B., Thurston, David E., Giles, Peter J. ORCID: https://orcid.org/0000-0003-3143-6854, Ashelford, Kevin ORCID: https://orcid.org/0000-0003-3217-2811, Walsby, Elisabeth J. ORCID: https://orcid.org/0000-0001-8523-5017, Fegan, Christopher D. ORCID: https://orcid.org/0000-0001-9685-0621, Pepper, Andrea G.S., Rahman, Khondaker Miraz and Pepper, Chris 2021. Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers. Haematologica 106 (4) , pp. 958-967. 10.3324/haematol.2019.238584

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Abstract

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB 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-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB 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-κB 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-κB 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-κB-driven cancers, particularly in the context of relapsed/refractory disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine
Additional Information:	This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Publisher:	Ferrata Storti Foundation
ISSN:	0390-6078
Date of First Compliant Deposit:	14 August 2020
Date of Acceptance:	24 March 2020
Last Modified:	07 Nov 2024 08:30
URI:	https://orca.cardiff.ac.uk/id/eprint/134213

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