Starting over a decade ago, LIMR researchers pioneered the development of small molecule inhibitors of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO), several of which are now being evaluated in oncology trials being conducted around the world. This drug class acts as adjuvants to improve the immune response in many settings of cancer therapy, including chemotherapy, radio-chemotherapy, radiotherapy and immunotherapy. Thus, interest in IDO inhibitors continues to grow as research proceeds to determine their most effective uses. As a result of ongoing basic research in the field, other enzymes related to IDO have been discovered at LIMR and elsewhere that advance ideas for development of second-generation drugs.
LIMR’s collaborative team has created the first pro-drug class of small molecule inhibitors that can be tuned to inhibit various subsets of the known IDO/TDO enzymes, representing new structure of matter for clinical development. No pro-drug claims for IDO/TDO enzyme inhibitors have been made in the field as yet. Present work is at the preclinical proof-of-concept stage.
IDO/TDO inhibitors are an area of broad interest in the treatment of diverse cancers, with preclinical and emerging clinical evidence that they can safely enhance the efficacy of chemotherapy, radiotherapy, radio-chemotherapy, immune checkpoint therapy, and cancer vaccines. The large global market for cancer drugs is expected to increase from $85 billion in 2016 to $155.6 billion by 2025, according to the research and consulting firm Transparency Market Research.
Intellectual property position
Pro-drug IDO/TDO inhibitor structures and uses: Patent pending.
Malachowski WP, Winters M, DuHadaway JB, Lewis-Ballester A, Badir S, Wai J, Rahman M, Sheikh E, LaLonde JM, Yeh S-R, Prendergast GC and Muller AJ. (2016) O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. Eur J Med Chem 108: 564-576.
Prendergast GC, Malachowski WP, DuHadaway JB and Muller AJ. (2017). Discovery of IDO1 inhibitors: From bench to bedside. Cancer Res 77: 6795-6811.
Winters M, DuHadaway JB, Pham KN, Lewis-Ballester A, Badir S, Wai J, Sheikh E, Yeh S-R, Prendergast GC, Muller AJ and Malachowski WP. Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. (Submitted)