CDK7 inhibitor THZ1 alleviates cytokine release syndrome through suppressing inflammatory transcription in activated macrophages

Cytokine release syndrome (CRS) is an uncontrolled inflammatory response that can be triggered in diseases or in treatments. Severe CRS can counteract the efficacy of therapy and lead to a life-threatening consequence if not reverse the related disorders. Using THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), we demonstrated a therapeutic potential of blocking CDK7 to disrupt the inflammatory transcription in activated macrophages. Data from murine models in vivo confirmed the potent efficacy of THZ1 to mitigate CRS that induced by bacterial/viral stimuli or by CART therapy without apparent tissue injury. Landscapes of super enhancers in macrophages revealed the central regulator of STAT1/STAT4 and the critical effector of IL-1, both of which were regulated at the transcriptional level via RNA polymerase II, the downstream of CDK7. These results indicate that CDK7 inhibition can be used as a promising candidate for treating CRS.