Combination small molecule inhibitors of IDO/TDO enzymes

Lead investigators: Alexander J. Muller, PhD and George C. Prendergast, PhD
Collaborator: William Malachowski, PhD, Bryn Mawr College

Unmet need

Immunometabolic adjuvants are needed that can broadly and safely leverage the therapeutic benefits of chemotherapy, radiotherapy and immunotherapy in diverse advanced human cancers.


LIMR scientists have synthesized second-generation “combi” or “pan” inhibitors that block the catalytic activity of the IDO1, IDO2 and/or TDO2 enzymes. 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.

Unique attributes

Starting more than a decade ago, LIMR scientists pioneered the discovery of small molecule inhibitors of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO), several classes of which are being studied in ongoing Phase 2 oncology trials worldwide. These immunometabolic adjuvants have been observed in many studies to improve the response of cancer chemotherapy, radio-chemotherapy, radiotherapy and immunotherapy. As a result of ongoing research in the field, LIMR scientists have developed second-generation inhibitors that can coordinately block the TDO2 and IDO2 enzymes also implicated in cancer (which can mediate bypass to IDO1 blockade).

Clinical applications

IDO/TDO inhibitors apply to the treatment of diverse cancers, with preclinical and emerging clinical evidence that they safely enhance the efficacy of chemotherapy, radiotherapy, radio-chemotherapy, immune checkpoint therapy and cancer vaccines.

Stage of development

Present work is at the preclinical proof-of-concept stage.

Intellectual property

Multiple issued and pending patents claiming structure of matter and medicinal uses. Several classes of protected structure of matter is available for licensing, including the first pro-drug inhibitors for these enzymes.

Collaboration opportunity

Preclinical development of protected IDO inhibitor structures and novel combination drug therapies including IDO inhibitors to treat cancer.

Relevant publications

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. (2019) Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. Eur J Med Chem 162:455-464.


Institutional contact: George C. Prendergast, PhD, LIMR President and CEO, 484.476.8475, [email protected]

IP manager contact: Heather Rose, PhD, JD, VP of Technology Licensing and Startups, Thomas Jefferson University, 215.503.0770, [email protected]