Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB

Abstract

NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Two NIK inhibitors and an isomeric control were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. Combination therapy targeting NIK and IKKbeta (as a main kinase of the classical NFkB pathway) represents a promising treatment strategy in MM. NIK inhibitors can also be useful tool for assessing the role of NIK and alternative NFkB pathway in different cells.

A small‐molecule inhibitor of NF‐κB‐inducing kinase (NIK) protects liver from toxin‐induced inflammation, oxidative stress, and injury

“…It has been reported that the in vivo pharmacokinetic properties of this class of NIK inhibitor are not optimal. In line with another report (14), multiple tandem, high doses of B022 are necessary to achieve in vivo inhibition of NIK‐or CCl 4 ‐induced liver injury and inflammation (rather than 1 or 2 doses). Therefore, further modifications to B022 are needed to achieve better in vivo pharmacokinetic properties.…”

“…It has been reported that the in vivo pharmacokinetic properties of this class of NIK inhibitor are not optimal. In line with another report (14), multiple tandem, high doses of B022 are necessary to achieve in vivo inhibition of NIK-or . B022 suppresses NIK-triggered liver inflammation and injury.…”

Osteoclasts—Key Players in Skeletal Health and Disease

“…Recent studies have shown that activating-mutations in the alternative NF-κB pathway are common in multiple myeloma, and play a role in tumor survival (189, 190). Since this pathway is also important for OC formation and function (191–193), its inhibition could also represent a powerful therapeutic strategy (194). …”

The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status

“…Finally, we determined the potential activity of specific NIK inhibitors 13,14 in those MCL cell lines resistant to CC-292 due to activation of the alternative NF-kB pathway. Z138 and MAVER-1 were treated for 6 days with two NIK inhibitors, AM-0216 (#16) and AM-0561 (#61), or with an isomeric control of AM-0216 [AM-0650 (#50)], in the presence or absence of 1 mM CC-292.…”