CD73 inhibitors
Inventors
Du, Xiaohui • Eksterowicz, John • Fantin, Valeria R. • Sun, Daqing • YE, Qiuping • Moore, Jared • Zavorotinskaya, Tatiana • BLANK, Brian R. • Rew, Yosup • Wu, Kejia • Zhu, Liusheng • Pham, Johnny • Kawai, Hiroyuki • Yeh, Chien-Hung
Assignees
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Publication Number
US-11130778-B2
Publication Date
2021-09-28
Expiration Date
Abstract
Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
Core Innovation
The invention relates to CD73 inhibitors and discloses CD73-targeting compounds of Formula (I), including pharmaceutically acceptable salts, solvates, stereoisomers, and isotopic variants. The disclosure provides broad substituent definitions and example chemical structures for the compounds of Formula (I), and the compounds are presented as acting on CD73 in a subject.
The disclosure addresses cancer treatment in connection with CD73 and adenosine signaling, including tumor immune suppression and immune resistance. Background information links CD73-mediated adenosine production to immune evasion and describes the CD39/CD73 axis in which CD73 functions as an ectonucleotidase that hydrolyzes AMP to adenosine, together with adenosine receptor signaling including P1 receptors (A1, A2A, A2B, A3).
The invention further provides pharmaceutical compositions containing the CD73-targeting compounds and methods of inhibiting CD73 by contacting CD73 with the compounds. Therapeutic indications explicitly include cancer, infections, and neurodegenerative diseases, with further cancer context described as CD73-expressing or CD73-upregulated tumors and possible combination therapy with a second therapeutic agent, including chemotherapeutic agents and immunotherapy agents.
The document also describes stereodefined small-molecule phosphonic acids and phosphonic-acid-containing heterocyclic scaffolds, including pyrazolo[3,4-d]pyrimidine, tetrazolyl, and dihydroxytetrahydrofuran motifs with defined stereochemistry. The compounds are exemplified by specific example structures and are presented within a claimed group for cancer treatment methods.
Claims Coverage
The consolidated claim coverage identifies independent claim content directed to treating cancer in a subject by administering a compound selected from a depicted group or Formula (I), including pharmaceutically acceptable salts. The inventive features center on administration of CD73-targeting or depicted phosphonic acid compounds for leukemia, lymphoma, or multiple myeloma, with dependent refinements specifying subtypes.
Treating leukemia, lymphoma, or multiple myeloma by administering a selected compound
A method of treating cancer in a subject, wherein the cancer is leukemia, lymphoma, or multiple myeloma, comprising administering to the subject a compound selected from the group consisting of CD73-targeting compounds or the depicted compounds, or a pharmaceutically acceptable salt thereof.
Leukemia subtype selection
The method applies to leukemia types selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, myelocytic leukemia, refractory anemia, preleukemia, chronic myelomonocytic leukemia (CMML), or hairy cell leukemia.
Lymphoma subtype selection
The method applies to lymphoma that is either Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Multiple myeloma subtype selection
The method applies to multiple myeloma-related disease types including smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, or solitary plasmacytoma.
Administered compound defined by the depicted chemical structure
The method uses a particular compound of the depicted group, Formula (I), or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is directed to treating leukemia, lymphoma, or multiple myeloma by administering a compound selected from a CD73-targeting or depicted chemical group, including pharmaceutically acceptable salts. The dependent refinements narrow the cancer subtypes and tie the administered compound to the depicted structure.
Stated Advantages
CD73 inhibition is presented in the context of cancer treatment and immune resistance.
The compounds are positioned for use against CD73-expressing or CD73-upregulated tumors.
Possible combination therapy with chemotherapeutic agents and immunotherapy agents is disclosed.
Documented Applications
Cancer.
Infections, including viral infection and parasitic infection.
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and autism.
A CD73 biochemical assay framework with IC50 (CD73_Biochem nM) table legend for examples 1–60.
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