BioCentury
ARTICLE | Distillery Therapeutics

Cancer

April 4, 2018 3:26 PM UTC

Patient sample, in vitro and mouse studies identified a BRD4 inhibitor that could help treat CLL. In B cells isolated from patients, BRD4 levels were higher than in B cells from healthy volunteers. Screening of BET bromodomain protein inhibitor tool compounds via in vitro binding assays, followed by optimization of a dimethylisoxazole-azaindole-based screening hit, yielded a compound that bound the bromodomain 1 and 2 units of BRD4 with Kd values of 1.7 and 6.1 nM, respectively. In patient-derived B cells alone or co-cultured with stromal cells, and in a human CLL cell line, the compound decreased proliferation compared with vehicle. In a transgenic mouse model of CLL expressing human T cell leukemia/lymphoma 1A (TCL1A), the compound decreased peripheral blood lymphocytes and leukemic cells in the spleen. In an adoptive transfer mouse model of CLL, the compound decreased tumor burden, spleen size, lymph node masses and the number of atypical neoplastic lymphocytes in the spleen and increased survival. In another adoptive transfer mouse model of CLL, the compound decreased peripheral blood lymphocytes and spleen size and increased survival compared with vehicle or Imbruvica ibrutinib. Next steps could include IND-enabling safety testing of the compound.

AbbVie Inc. and Johnson & Johnson market Imbruvica, a Bruton’s tyrosine kinase (Btk) inhibitor, for CLL, other lymphomas and leukemias and graft-versus-host disease (GvHD), and have the compound in Phase I/II through Phase III testing for multiple other cancers...

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