2. Academic Validation
  3. The cyclin dependent kinase (CDK)7 inhibitor BS-181 inhibits pathogenic Cryptococcus species, causing G2/M arrest and a splicing defect

The cyclin dependent kinase (CDK)7 inhibitor BS-181 inhibits pathogenic Cryptococcus species, causing G2/M arrest and a splicing defect

  • Virulence. 2026 Dec;17(1):2629100. doi: 10.1080/21505594.2026.2629100.
Pooja Sethiya 1 2,  Desmarini Desmarini 1 2,  Bethany Bowring 1 2,  Hue Dinh 3,  Amy K Cain 3,  Chirag Parsania 4 5 6,  Catriona L Halliday 2 7,  Sharon C-A Chen 2 7 8,  Kim Hewitt 9,  Julianne Teresa Djordjevic 1 2 8
Affiliations

Affiliations

  • 1 Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW , Australia.
  • 2 Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW , Australia.
  • 3 ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, North Ryde, NSW, Australia.
  • 4 Cancer & Gene Regulation Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
  • 5 Centre for Rare Diseases & Gene Therapy Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
  • 6 School of Medical Sciences, Faculty of Medicine & Health, The University of Sydney, Camperdown, NSW, Australia.
  • 7 Centre for Infectious Diseases and Microbiology Laboratory Services, Institute for Clinical Pathology and Medical Research, New South Wales Health Pathology, Westmead Hospital, Westmead, NSW.
  • 8 Department of Infectious Diseases, Westmead Hospital, Westmead, NSW, Australia.
  • 9 Westmead Bioresources Facility and Scientific Platforms, Westmead Institute for Medical Research, Westmead, NSW, Australia.
PMID: 41701636 DOI: 10.1080/21505594.2026.2629100
Abstract

The Fungal priority pathogen and basidiomycete, Cryptococcus neoformans (Cn), causes lung and brain Infection in predominantly immuno-compromised individuals and there is an urgent need for new treatment options. The pyrazolopyrimidine-based cyclin dependent kinase (CDK)7 inhibitor, BS-181, has Anticancer properties, but its Antifungal activity has not been investigated. We show that cryptococcal CDK7 more closely resembles the human enzyme than that of ascomycetes, and that BS-181 inhibits its activity. BS-181 inhibited growth of both Cn and Cryptococcus gattii (Cg), but not ascomycete fungi and delayed progression through the G2/M phase of the cell cycle. Transcriptomic analysis revealed that BS-181 induces splicing defects leading to elevated intron retention within the transcriptome and also suppresses translational processes. BS-181 displayed additive or synergistic activity with licensed antifungals against laboratory and clinical Cn and Cg strains, most notably with amphotericin B where synergy (2-4-fold reduction in the amphotericin B MIC) was achieved using low-sub micromolar concentrations of BS-181. Compared with either drug alone, BS-181-AmB combination therapy provided greater protection against Cn Infection in a wax moth model (p ≤ 0.032) and extended survival of Cn-infected mice. These findings demonstrate that CDK7 inhibitors, already of interest as Anticancer agents, could be repurposed to prevent or treat opportunistic Fungal infections in Cancer patients when combined with licensed antifungals limited by either toxicity or resistance.

Keywords

BS-181; CDK7 inhibitor; Cryptococcus gattii; Cryptococcus neoformans; antifungal; cell cycle; splicing; transcription; translation.

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