CMPK2 inhibitors vs. chronic inflammation

“It has been obvious for some time that, when available, drugs that turn off the NLRP3 inflammasome, but not other inflammasomes, will be very useful for treating a variety of inflammatory disorders, from osteoarthritis to Alzheimer’s disease and cancer,” said Dr. Zhenyu Zhong, first author and a UC San Diego School of Medicine postdoctoral researcher. “Until now, it was not clearly understood how environmental stress and tissue injury activate the NLRP3 inflammasome and, without such knowledge, it was impossible to rationally design specific inhibitors of the NLRP3 inflammasome.”

Interleukin 1β (IL-1β) is an inflammatory cytokine or hormone responsible for beneficial and adverse effects of inflammation. Normally, IL-1β is produced in very low amounts, but in response to injury, environmental stress, infection or chronic inflammation, production of IL-1β is highly increased. Production and secretion of IL-1β is regulated by inflammasomes.

In addition to an enzyme called caspase-1, inflammasomes contain sensor proteins that respond to different signals generated by cell stress, tissue injury or infectious organisms. One of the most important and versatile sensors is NLRP3, which is responsible for inflammasome activation and IL-1β production in response to tissue injury or microparticles, including asbestos and silica dust. NLRP3 activators include microcrystals of cholesterol or uric acid, which trigger the inflammation associated with atherosclerosis or gout, respectively.

“CMPK2 inhibitors will only impact inflammation that depends on activation of the NLRP3 inflammasome. That is expected to include gout and osteoarthritis … It should also include Alzheimer’s disease,” note Zhong and Dr. Michael Karin, Distinguished Professor of Pharmacology and Pathology.

“CMPK2 stands for cytosine (or deoxycytosine) monophosphate kinase 2. CMPK2 belongs to the family of nucleotide kinases, so it is an enzyme that is targeted to mitochondria where it converts dCMP to dCDP, which is then converted to dCTP, one of the building blocks of DNA synthesis,” explain Karin and Zhong, who highlight the critical role that CMPK2 plays in the activation of NLRP3 and IL-1β production, and subsequently in chronic inflammatory disorders.

“I predict that specific inhibitors of CMPK2 can be easily and rapidly developed,” noted Karin, who was senior author on the Nature paper. “Once available, such compounds may provide us with new treatments for many diverse untreatable and common illnesses, including osteoarthritis, Alzheimer’s disease and lung cancer.”

According to Zhong and Karin, “We first found that NLRP3 inflammasome activation requires new mitochondrial DNA synthesis. We also found that IRF1, a nuclear transcription factor, is needed for mitochondrial DNA synthesis and NLRP3 inflammasome activation. We then looked for IRF1 target genes that may be involved in the stimulation of mitochondrial DNA synthesis and found CMPK2.”

As Karin explains, in gout and osteoarthritis, CMPK2 inhibitors might reduce inflammation, pain and tissue damage. In Alzheimer’s and Parkinson’s disease, they may slow progression and loss of cognitive function. A recent unaffiliated trial showed that administering an antibody targeting IL-1β reduces the likelihood of a second cardiac infarction in patients who already have undergone one heart attack. Further analysis of the data found that it had an even greater positive effect in patients with lung cancer.

“Unlike IL-1β antibody, which blocks IL-1β that is produced in response to bacterial infections, the CMPK2 inhibitor will only prevent IL-1β induction in response to tissue injury or micro particles,” Karin mentioned.

“A CMPK2 inhibitor will only inhibit activation of the NLRP3 inflammasome, which means that only NLRP3-dependent IL-1β synthesis is inhibited. An IL-1β antibody will block all IL-1β molecules regardless of how those molecules are made,” Zhong and Karin add. “Development of a specific CMPK2 inhibitor should not take very long. There are quite a few nucleotide kinase inhibitors available right now. However, we first need to determine that CMPK2 inhibition is safe, which is something that we are working on right now.”

“The most exciting aspect of the research is that it can lead to new treatment options for Alzheimer’s disease and other neurodegenerative disorders that depend on activation of the NLRP3 inflammasome,” they conclude.

Co-authors include Shuang Liang, Elsa Sanchez-Lopez, Feng He, Shabnam Shalapour, Jerry Wong, Bernd Schnabl, Tatiana Kisseleva, UC San Diego; Xue-jia Lin, UC San Diego and Jinan University; Siyuan Ding and Harry B. Greenberg, Stanford University and VA Palo Alto Health Care System; Ekihiro Seki, Cedars-Sinai Medical Center; and Andrea L. Hevener, UC Los Angeles.