TR-2018-09
Re-engineering Dasatinib into an Immuno-synergic Drug
Ariel Fernandez; L. Ridgway Scott. 28 October, 2018.
Communicated by L. Ridgway Scott.
Abstract
Immune checkpoint blockers revolutionized cancer therapy. Yet, they met only modest success when treating tumors where regulatory T cells recruited at the tumor periphery overwhelmingly suppress the adaptive immune response. To achieve lasting cure, we propose immuno-tuning combinations with purposely engineered targeted agents that block indirect tumor-induced immunosuppression without adversely impacting the adaptive response. In particular, we propose a redesign of dasatinib with three objectives: (1) to remove its nanomolar affinity towards LCK, a major signal transducer in the activation of T cells, thereby avoiding interference with the adaptive immune response, (2) to enhance its affinity towards c-KIT, a crucial receptor in the recruitment of regulatory T cells, thereby preventing tumor recruitment of immuno-modulatory elements, and (3) to enhance its affinity towards
c-SRC, a major cancer target, thereby promoting a higher antigenic activity. We propose to combine this dasatinib variant with an immune checkpoint inhibitor to enhance the tumor susceptibility to immunotherapy.
Original Document
The original document is available in PDF (uploaded 28 October, 2018 by
L. Ridgway Scott).
