Necrostatins - Inhibitors of Necroptosis
Bacterial infections are a cause of a major medical concern in the US as the rates of the hospital-associated infections remain high (estimated at ~4.5 cases per 100 visits) and can lead to serious disability and, in ~5% of the cases, to the death. Gram-negative bacteria (GNB) are particularly dangerous as they are known to possess multiple mechanisms to evade immune responses and show increased ability to develop resistance to antibiotics. Innate immune cells detect GNBs through a variety of mechanisms, but sensing of the lipopolysaccharide (LPS) component of the GNB bacterial wall by TLR4 is recognized as being particularly important for mounting effective innate immune responses.
Inflammation and cell death are two host responses important in bacterial infections. Both processes are essential components of the host innate immunity and benefit the infected host by limiting the numbers of pathogen harboring cells (cell death) while promoting the response of the immune system to the infection (inflammation). However, in some cases, these processes may also be detrimental for the host. Some classes of bacterial pathogens can activate cell death and deplete responding innate immune cells populations (eg macrophages) and, thus, evade immune responses. Furthermore, hyperactivation of inflammation and cell death can lead to extremely acute organ failure and death of the host (septic shock). Thus, understanding the control of these processes in the context of pathogenic infections is crucial for developing therapeutic strategies to protect the host from lethal sepsis without compromising bacterial clearance.
RIPK1 and RIPK3 are a family of Ser/Thr kinases with important roles in activation of necroptotic cell death pathway by multiple stimuli, including tumor necrosis factor alpha (TNFα) family of cytokines, interferons (IFNs), and TLR ligands. In TNF stimulated cells, RIPK1 is recruited to the receptor complex and contributes to inflammatory gene expression and cell survival in a ubiquitination-dependent fashion. However, the role of the kinase activities of RIPK1 and RIPK3 in innate immune responses is still unclear.
Degterev and coworkers have described the development of necrostatins, a class of efficient small molecule inhibitors of necroptosis. Necrostatin-1 (Nec-1) displayed exclusive selectivity toward RIPK1 kinase. Recently, our collaborative work, led by Malek Najjar, a Pharmacology & Experimental Pharmacology PhD student established that the BCR-ABL inhibitor and anti-leukemic FDA approved drug ponatinib is a first in class dual potent inhibitor of RIPK1 and RIPK3. We also further described design strategies that utilize the ponatinib scaffold to develop two new classes of inhibitors, each with greatly improved selectivity toward RIPK1, which outline promising candidate molecules for targeting RIPK1-driven inflammatory pathologies. Malek continues to focus his work on understanding the role of RIPK1 kinase as a drug-targetable contributor to innate immune responses to LPS in vitro and in vivo.
Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin J, Yuan J, Balachandran S, Cuny GD, Degterev A. 2015. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. Epub ahead of print.