Defining cyclin-dependent kinase 9 as a therapeutic target for inflammatory bowel disease

Student thesis: Doctoral ThesisDoctor of Philosophy


The treatment of auto-inflammatory disorders, such as inflammatory bowel disease (IBD), are often limited by unresponsiveness to single cytokine blockade, namely anti-TNF therapy. This is particularly important as treatment failure in IBD is associated with significant morbidity. The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiple genes such as the proinflammatory cytokines IFN-γ and TNF-α. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging therapeutically. P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet, activates gene transcription by phosphorylating RNA polymerase II and its activity can be suppressed using CDK9 inhibitors.

In this thesis, it was shown that CDK9 inhibition resulted in diminished serine 2 phosphorylation of RNA polymerase II with associated suppression of IFN-g and TNF-a production. Systemic CDK9 inhibition led to histological improvement of immune-mediated murine IBD, associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A.

Transcriptomics data from human IBD colonic CD4+ T cells demonstrated that CDK9 inhibition preferentially repressed genes that were highly induced by P-TEFb, and these genes were often associated with T-bet enhancers. CDK9 inhibition resulted in significant repression of immune pathways implicated in numerous immune-mediated and inflammatory disorders.

CDK9 inhibition was effective at suppressing cytokine production by colonic lymphocytes from patients with anti-TNF resistant disease. Furthermore, transcripts repressed by CDK9 inhibition were highly expressed in anti-TNF resistant IBD raising expectations that CDK9 inhibitors may be efficacious in this difficult-to-treat cohort of patients. Collectively, these findings provide new insight into the therapeutic role of CDK9 inhibition for IBD, which has potential for rapid translation to the clinic.
Date of Award1 May 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorGraham Lord (Supervisor) & Peter Irving (Supervisor)

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