Abstract
Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.
Highlights
NF-κB transcription factors are aberrantly activated in most human cancers, including multiple myeloma (MM), where they drive oncogenesis, therapy resistance and malignant cell survival largely by upregulating genes that suppress cancer-cell apoptosis
We previously reported that DTP3 displayed no significant off-target effects in a panel of 142 human kinases, and that its therapeutic activity in sensitive MM cell lines was completely abrogated by the RNA interference-mediated inhibition of MKK7, its pharmacological target, suggesting it exhibits high target specificity [11]
At higher concentrations (i.e., 100 μM), DTP3 exhibited a weak antagonist effect on Sigma (Supplementary Fig. 1D). While these weak in-vitro interactions of DTP3 with Sigma and MOP receptors identify a potential for secondary pharmacological activities, these effects were observed at relatively high drug concentrations, significantly higher than the therapeutically effective in-vivo plasma concentrations [11], and are not relevant, at least from a regulatory perspective, for a clinical drug candidate in oncology
Summary
NF-κB transcription factors are aberrantly activated in most human cancers, including multiple myeloma (MM), where they drive oncogenesis, therapy resistance and malignant cell survival largely by upregulating genes that suppress cancer-cell apoptosis. Since constitutive NF-κB activity drives oncogenesis by upregulating antiapoptotic genes [2,10], we sought to overcome this barrier by targeting the non-redundant, cancer-specific downstream effectors of the oncogenic NF-κB survival function, rather than NF-κB itself [11] We tested this principle in MM, an incurable plasma-cell malignancy and the paradigm for NF-κB-driven cancers [12]. Due to its mode of action, operating downstream of NF-κB, DTP3 exhibits the capacity to synergise with bortezomib and bypass drug resistance to conventional anti-MM therapies, including steroids, IMiDs and proteasome inhibitors To translate these advantageous pharmacological properties into healthcare benefit, we sought to initiate clinical trials of DTP3 in patients with relapsed or refractory MM. Due its cancer-selective pharmacology and capacity to bypass drug resistance and synergise with bortezomib, DTP3 represents a significant clinical opportunity, which could translate into a safe and effective anticancer therapeutic to treat patients with relapsed/refractory MM and potentially other recalcitrant NF-κB-driven cancers
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