CN-116261459-B - Compositions and methods for inhibiting YTHDF a1

Abstract

Compositions and methods for attenuating YTHDF a activity, and compositions and methods for promoting an immune response are provided. For example, an YTH N6-methyladenosine RNA binding protein 1 (YTHDF 1) reducer is provided, wherein the reducer comprises a compound that, when bound to YTHDF1, binds to at least one residue of YTHDF.

Inventors

• LUO CHENG
• XU MENG
• CHEN SHIJIE
• LI YILIN
• CHEN YANTAO
• JIANG HUALIANG
• CHEN KAIXIAN
• JIANG ZHANPENG

Assignees

• 中国科学院上海药物研究所
• 杭州领知医药科技有限公司
• 上海康黔生物科技有限公司

Dates

Publication Date

20260508

Application Date

20210708

Priority Date

20200709

Claims (17)

1. 1. Use of a modified antigen presenting cell (mAPC) in the manufacture of a medicament, said mAPC having been treated with a YTH N6-methyladenosine RNA binding protein 1 (YTHDF 1) attenuation agent, Wherein, the The YTHDF1 reducer is the following compound or pharmaceutically acceptable salt thereof: , The medicament is for treating cancer in a subject in need thereof, The mAPC is a modified dendritic cell (mDC).
2. 2. The use of claim 1, wherein the cancer is a hematological tumor.
3. 3. The use of claim 1, wherein the cancer is lymphoma.
4. 4. The use of claim 1, wherein the cancer is a solid tumor.
5. 5. The use according to claim 1, wherein the cancer is selected from the group consisting of melanoma, breast cancer, lung cancer, ovarian cancer, liver cancer, cervical cancer, colon cancer, renal cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, gastric cancer, pancreatic cancer and testicular cancer.
6. 6. The use of claim 1, wherein the cancer is brain cancer.
7. 7. The use of claim 1, wherein the cancer is colorectal cancer.
8. 8. The use of claim 1, wherein the cancer is skin cancer.
9. 9. The use of claim 1, wherein the cancer is uterine cancer.
10. 10. The use of claim 1, wherein the cancer is leukemia.
11. 11. The use according to claim 1, wherein the medicament further comprises a second active ingredient selected from the group consisting of an anti-PD-L1 antibody or antigen-binding portion thereof, an anti-PD-1 antibody or antigen-binding portion thereof, an anti-CTLA-4 antibody or antigen-binding portion thereof, and an IDO inhibitor.
12. 12. The use according to claim 11, wherein the second active ingredient is selected from the group consisting of palbociclib, nal Wu Liyou mab, cimipran Li Shan antibody, atilizumab, avermectin, divali You Shan antibody, ipilimab and/or an antigen-binding fragment of any of the foregoing.
13. 13. The use according to claim 11, wherein the second active ingredient is contained in a separate container and is not mixed with the YTHDF reducer.
14. 14. Use of a composition comprising a YTH N6-methyladenosine RNA binding protein 1 (YTHDF 1) attenuation agent and a second active ingredient in the manufacture of a medicament, wherein, The YTHDF1 reducer is the following compound or pharmaceutically acceptable salt thereof: , the second active ingredient is an anti-PD-L1 antibody or an antigen-binding portion thereof, The medicament is for treating melanoma in a subject in need thereof.
15. 15. The use of claim 14, comprising a pharmaceutically acceptable carrier.
16. 16. The use according to claim 14, wherein the second active ingredient is selected from the group consisting of atilizumab, avermectin and rivaroubriot You Shan.
17. 17. The use according to claim 14, wherein the second active ingredient is contained in a separate container and is not mixed with the YTHDF reducer.

Description

Compositions and methods for inhibiting YTHDF a1 Background Spontaneous T cell sensitization against tumor neoantigens is critical for the clinical efficacy of immunotherapy. In many patients, however, neoantigen recognition is insufficient to induce the sustained T cell response required for complete tumor rejection. Identification of molecular pathways that affect the immune response of tumor neoantigens can provide targets for improving the response of immunotherapy. For example, m 6 a is the most abundant internal mRNA modification responsible for post-transcriptional regulation of mRNA of multiple cell types. In addition, m 6 a can affect mRNA translation efficiency through family protein 1 (YTHDF 1) where the m 6 a binding protein comprises an YTH domain. Previous studies have shown that attenuating YTHDF1 activity in various cells of the immune system (e.g., antigen presenting cells) can help induce a sufficient and sustained anti-tumor immune response. Effective compositions and methods for attenuating YTHDF's activity remain highly desirable. Disclosure of Invention The present application provides compositions and methods for attenuating YTHDF1 activity. The application also provides modified antigen presenting cells (mAPC), such as modified dendritic cells, having enhanced activity. The compositions and mAPC of the present application are useful for one or more purposes of activating APCs (such as DCs), generating immune cells with enhanced anti-tumor activity, preventing and/or reversing depletion of immune cells (such as T cells), treating a disease, disorder or condition associated with antigen expression in a subject in need thereof, treating cancer in a subject in need thereof, stimulating T cell-mediated immune responses to cancer cells and/or tumor antigens in a subject in need thereof, providing anti-tumor immunity in a subject in need thereof, increasing and/or improving proliferation and/or activity of tumor-infiltrating T cells, increasing and/or improving proliferation and/or activity of tumor-specific T cells, increasing production of cytokines by T cells, 12) enhancing anti-tumor response by tumor immunotherapy, 13) inhibiting tumor growth, inhibiting proliferation of tumor cells, and/or killing tumor cells. The application also provides methods and compositions for enhancing an immune response that combine the YTHDF reducer of the application and a second active agent, such as an immune checkpoint inhibitor. YTHDF1, a member of the YTH domain family, is a "reader" modified by m 6 A. For example, YTHDF a helps to increase the translation efficiency of mRNA by interacting with the translation initiation factor. Furthermore, a deregulation of YTHDF1 can break the expression balance between proto-oncogenes and tumor suppressors, suggesting a link between YTHDF1 and tumorigenesis. Over-expression of YTHDF1 has been reported to be associated with some malignant tumors such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). In addition, ythdf 1-deficient (Ythdf 1 -/-) mice were found to exhibit an improved anti-tumor immune response, suggesting YTHDF1 is a new potential therapeutic target. YTHDF1 was also found to be involved in the expression of T cell depletion marker genes. Mice lacking YTHDF a1 in T cells show better anti-tumor immunity against lymphomas, solid tumors (such as melanoma and colon cancer) and other types of cancer. Tumor-infiltrating T cell function was enhanced in YTHDF defective mice. In addition, T cell depleted differentiation was rescued toward the fate of memory-like or stem cell-like CD8 + T cells. In one aspect, the application provides an agent for attenuating YTH N6-methyladenosine RNA binding protein 1 (YTHDF 1), which agent comprises a compound that, when bound to YTHDF1, binds at least one residue corresponding to residues 372-392, 479-494 and 526-535 of amino acid residues selected from SEQ ID NO. 1. In some embodiments, the compound comprising the YTHDF1 attenuation agent binds at least one residue when bound to YTHDF, corresponding to the residues N378, F382, W384, F480, and H528 of SEQ ID NO. 1. In some embodiments, a compound comprising YTHDF1 reducer is capable of blocking the binding of YTHDF1 to m 6 a. In some embodiments, the compound comprising YTHDF a attenuating agent does not substantially compete with m 6 a for binding YTHDF1. In some embodiments, YTHDF1 attenuators include compounds of formula I, prodrugs, metabolites, derivatives, or pharmaceutically acceptable salts, esters, or amides of any of the foregoing: (formula 1), wherein R 1 is selected from the group consisting of C 1-50 hydrocarbyl, C 1-50 substituted hydrocarbyl, C 1-50 heterohydrocarbyl, and C 1-50 substituted heterohydrocarbyl. In some embodiments, R 1 in formula I is (CO) -R 2, and R 2 is optionally substituted alkenyl. In some embodiments, R 2 is ch=ch—r 3, and R 3 is optionally substituted aryl. In some embodiments, R 3 is a compound of formula IIWherein A is op