THIOIMIDAZOLINE BASED COMPOUNDS REVERSE GLUCOCORTICOID RESISTANCE IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA  — ASN Events
  1. Schedule
  2. Afternoon Tea/Poster Session
  3. THIOIMIDAZOLINE BASED COMPOUNDS REVERSE GLUCOCORTICOID RESISTANCE IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA 

THIOIMIDAZOLINE BASED COMPOUNDS REVERSE GLUCOCORTICOID RESISTANCE IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA  (#153)

Cara E Toscan 1 2 3 , (Duohui) Vincent Jing 1 2 , Tim Failes 1 4 , Greg Arndt 1 4 , Marwa Rahimi 3 , Shelli McAlpine 5 , Richard Lock 1 2
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. School of Women's and Children's Health, UNSW, Sydney, NSW, Australia
  3. School of Chemistry, UNSW, Sydney, NSW, Australia
  4. ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia, Sydney, NSW, Australia
  5. School of Chemsitry, UNSW, Sydney, NSW, Australia

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Glucocorticoids (e.g. dexamethasone, prednisolone) form a critical component of chemotherapy regimens for paediatric ALL and the initial response to glucocorticoid therapy is a major prognostic factor, where resistance is predictive of poor outcome. We have previously established a clinically relevant ALL xenograft model, in which in vitro and in vivo dexamethasone sensitivity significantly correlate with patient outcome. In this study we used a high throughput screen (HTS) to identify compounds that reverse glucocorticoid resistance in a xenograft derived from a chemoresistant paediatric ALL.

The HTS identified four thioimidazoline-containing compounds that showed little activity alone,  but when combined with dexamethasone caused a marked decrease in cell viability. The lead compound, GCS3, exhibits a longer half-life than the standard chemotherapeutic vincristine, and requires a functional glucocorticoid receptor to sensitise cells to glucocorticoids. The sensitising effect is specific to glucocorticoids, with synergy also observed when GCS3 was combined with the glucocorticoid, prednisolone, but not with other chemotherapeutics. Synergy was observed in a broad range of dexamethasone-resistant and –sensitive xenografts representative of B-ALL and T-ALL. GCS3 in combination with dexamethasone was shown to upregulate the pro-apoptotic protein, Bim, and significantly increase the binding of the glucocorticoid receptor to a novel intronic binding site in Bim.

The biological evaluation of 36 thioimidazoline analogues, 20 of which we synthesized, indicates that thioimidazoline alone does not have any dexamethasone sensitizing effect, but altering this substructure results in complete loss of activity. SAR analysis has identified that the most effective dexamethasone sensitizers contain a thioimidazoline acetamide substructure with a large hydrophobic moiety on the acetamide. In conclusion, using a clinically relevant xenograft model and a HTS, this study has identified a novel class of compounds that are able to reverse glucocorticoid resistance in multiple ALL subtypes.