Proteolysis-targeting chimeric molecules (PROTACs) that induce degradation of indoleamine 2,3-dioxygenase (IDO) protein
Inventors
Schiltz, Gary E. • Wainwright, Derek A.
Assignees
Publication Number
US-12311029-B2
Publication Date
2025-05-27
Expiration Date
2041-07-02
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Abstract
Disclosed are proteolysis-targeting chimeric molecules (PROTACs) that induce degradation of IDO protein. The disclosed PROTACs typically include a first targeting moiety that binds to IDO (Miro). The first targeting moiety typically is linked via a bond or a linker (L) to a second targeting moiety that binds to an E3 ubiquitin ligase (ME3). As such, the disclosed PROTACS may be described as having a formula MIDO-L-ME3 or ME3-L-MIDO.
Core Innovation
The invention discloses proteolysis-targeting chimeric molecules (PROTACs) that induce degradation of the indoleamine 2,3-dioxygenase (IDO) protein. These PROTACs are hetero-bifunctional compounds that include a first moiety (MIDO) that binds to IDO and a second moiety (ME3) that binds to an E3 ubiquitin ligase, the two being covalently joined by a bond or linker (L). The disclosed PROTACs can be generally represented as MIDO-L-ME3 or ME3-L-MIDO.
The problem addressed by the invention is the need for a more effective pharmacological strategy to neutralize IDO, due to its critical immunosuppressive role in cancer progression, particularly in glioblastoma multiforme (GBM). Existing enzyme inhibitors for IDO have failed in clinical trials, demonstrating the futility of relying solely on enzymatic inhibition, as both enzymatic and non-enzymatic functions of IDO contribute to disease.
The disclosed compounds bind with high affinity to IDO and recruit an E3 ubiquitin ligase, resulting in polyubiquitination and subsequent proteasomal degradation of IDO. By removing IDO protein from cells, these PROTACs abolish all immunosuppressive effects of IDO, regardless of whether the effect depends on its enzymatic activity. The invention includes detailed chemical structures and synthesis procedures of representative PROTACs, as well as their pharmaceutical compositions and methods of use in treating conditions associated with IDO expression, such as various cancers.
Claims Coverage
There is one independent claim in this patent, which covers a method featuring a new class of PROTAC-based therapeutics targeting IDO in cancer treatment.
Method of treating cancer with an IDO-targeting PROTAC pharmaceutical composition
This inventive feature covers: - Administration of a pharmaceutical composition to a subject with cancer. - The pharmaceutical composition comprises: - A molecule having a formula MIDO-L-ME3, in which: - MIDO is a moiety that binds to indoleamine 2,3-dioxygenase (IDO) - L is a bond or a linker covalently attaching MIDO and ME3 - ME3 is a moiety that binds to an E3 ubiquitin ligase - A suitable pharmaceutical carrier, excipient, or diluent. - The composition requires that MIDO-L-ME3 has a specified chemical structure, as detailed in the claim. This method is not restricted to a specific cancer type and encompasses PROTAC molecules that specifically induce IDO degradation via recruitment of an E3 ligase, enabled by the defined architecture of MIDO-L-ME3.
The claim coverage centers on a novel therapeutic method employing PROTAC molecules that link an IDO-binding moiety with an E3 ubiquitin ligase recruiter, resulting in targeted degradation of IDO for cancer treatment.
Stated Advantages
The disclosed PROTACs may be effective in inhibiting the growth of cells that express IDO, including various types of cancer cells.
The disclosed PROTACs abolish all immunosuppressive effects of IDO, including enzymatic- and non-enzymatic dependent functions.
The PROTACs may not inhibit the growth of cells that do not express IDO, providing selectivity.
The disclosed PROTACs are applicable to all forms of cancer and non-cancerous cells that also express IDO under pathologic circumstances.
The PROTACs may be formulated and administered in different pharmaceutical compositions and via various routes.
Documented Applications
Treatment of diseases and disorders associated with IDO activity, such as cell proliferation diseases including cancers.
Treatment of specific cancers, including glioblastoma multiforme (GBM), multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, cancer of the central nervous system, melanoma, ovarian cancer, renal cancer, uterine cancer, prostate cancer, pancreatic cancer, and breast cancer.
Use in pharmaceutical compositions comprising the PROTACs for inhibiting growth of cancer cells.
Administration methods involving combination therapy with immunotherapy agents such as anti-PD1 or anti-PD-L1 antibodies.
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