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EA-053296-B1 - Phospholipid Ether Conjugates as Drug Carriers for Cancer Targeting

EA053296B1EA 053296 B1EA053296 B1EA 053296B1EA-053296-B1

Abstract

The present invention relates to therapeutic compounds capable of targeting a broad range of tumor cells. Furthermore, the present invention relates to compositions containing the therapeutic compounds, methods for producing the therapeutic compounds, and methods for treating cancer involving the administration of the therapeutic compounds.

Inventors

  • Лонгкор Джеррод
  • ПИНЧУК Анатолий
  • Хувер Рэндалл
  • Хуан Чжунпин

Assignees

  • СЕЛЛЕКТАР БАЙОСАЙЕНСИЗ, ИНК.

Dates

Publication Date
20260504
Application Date
20200911
Priority Date
20190912

Claims (14)

  1. Item 19. The method according to any one of items 10-15, wherein the cancer is melanoma, lung cancer, colorectal cancer, breast cancer or a combination thereof, and wherein the compound is a compound of formula (I-c) or a pharmaceutically acceptable salt thereof. The above description of specific aspects discloses the general essence of the present invention so fully that others, using knowledge in the art, can easily modify and/or adapt it for various applications of such specific aspects without undue experimentation, without departing from the general concept of the present disclosure. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the principles and recommendations presented herein. It should be understood that the phraseology or terminology in this document is for the purpose of description and not limitation, so that the terminology or phraseology of the present description should be interpreted by one skilled in the art in light of the disclosure and recommendations. The breadth and scope of the present disclosure should not be limited by any of the above-described illustrative aspects, but should be defined only in accordance with the following claims and their equivalents. All publications, patents, patent applications and/or other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application and/or other document were individually indicated to be incorporated by reference for all purposes. CLAUSES OF THE INVENTION 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, © Me 3 N Θ —ЬСВД—Q 1 —L—Q 2 -Z x ' η (I), having structures of formula (I-a), where η is 2-20, Q 1 is , n U ? NY Ν A t P 2 - no no no L-Q represents he about he or , And Z is a poly(IgG)-like kinase 1 (PLK-1) inhibitor, a tubulin polymerization inhibitor, a tubulin stabilizer, an antineoplastic agent, or a eukaryotic translation initiation factor 4 (EIF4) inhibitor.
  2. 2. The compound of claim 1, wherein Z is a PLK-1 inhibitor or an antineoplastic agent selected from the group consisting of monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and monomethyl auristatin D (MMAD).
  3. 3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, ® Me 3 N O Θ LE (U^O—ЬСНН—Q 1 —L—Q 2 —Z v / η (I) having the structure of formula (I-b), where η is 18, Q 1 is -36053296 LQ 2 is where R x represents H or halogen, and Z is an analogue of combretastatin A-4.
  4. 4. A compound according to claim 1 or 3, which is selected from the group consisting of - 37 053296 or a pharmaceutically acceptable salt thereof.
  5. 5. A compound selected from the group consisting of: - 38 053296 - 39 053296 or a pharmaceutically acceptable salt thereof.
  6. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  7. 7. The use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in an effective amount for the treatment of cancer in a subject in need thereof.
  8. 8. The use according to claim 7, wherein the cancer is melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.
  9. 9. The use according to claim 7 or 8, wherein the lung cancer is small cell lung cancer, non-small cell lung cancer, or a combination thereof, melanoma includes superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, amelanotic melanoma, nevoid melanoma, spitzoid melanoma, desmoplastic melanoma, or a combination thereof, colorectal cancer includes adenocarcinoma, or breast cancer includes invasive ductal carcinoma of the breast, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof.
  10. 10. The use according to any one of claims 7 to 9, wherein the cancer contains cancer stem cells.
  11. 11. The use according to any one of claims 7 to 10, wherein the cancer comprises metastatic cancer cells.
  12. 12. The use according to any one of claims 7 to 11, wherein the cancer contains circulating tumor cells.
  13. 13. The use according to any one of claims 7 to 12, wherein the cancer is melanoma, lung cancer, colorectal cancer or a combination thereof and wherein the compound is a compound of formula (I-a) or a pharmaceutically acceptable salt thereof.
  14. 14. The use according to any one of claims 7-12, wherein the cancer is breast cancer, wherein the subject (1) is estrogen receptor positive, (2) is both estrogen receptor negative and progesterone receptor negative, (3) expresses HER2 (HER2+), (4) does not express HER2 (HER2-), or shows a combination thereof. -

Description

Link to related applications This application claims priority from U.S. Provisional Patent Application No. 62/899,611, filed September 12, 2019, U.S. Provisional Patent Application No. 62/899,615, filed September 12, 2019, U.S. Provisional Patent Application No. 62/899,618, filed September 12, 2019, U.S. Provisional Patent Application No. 62/946,870, filed December 11, 2019, U.S. Provisional Patent Application No. U.S. Patent Application No. 62/956,844, filed January 3, 2020, and U.S. Provisional Patent Application No. 62/956,907, filed January 3, 2020, the contents of which are incorporated herein by reference. Field of technology to which the present invention relates The present invention relates to therapeutic compounds capable of targeting a broad range of tumor cells. Furthermore, the present invention relates to compositions containing the therapeutic compounds, methods for producing the therapeutic compounds, and methods for treating cancer involving the administration of the therapeutic compounds. Prior art of the present invention In 2018, 18 million people worldwide were diagnosed with cancer, and 9.6 million people died from cancer. In the United States, approximately 40% of all people will develop cancer during their lifetime. As of 2018, lung cancer (2.09 million cases), breast cancer (2.09 million cases), colorectal cancer (1.80 million cases), prostate cancer (1.28 million cases), skin cancer (non-melanoma) (1.04 million cases), and stomach cancer (1.03 million cases) were the most common cancers. Despite many available treatments, cancer remains the second leading cause of death worldwide. Cancer results from unrestricted cell division. Healthy cells have checkpoints that prevent unlimited cell division. Some examples of such checkpoints include nutrient availability, DNA damage, and contact inhibition (i.e., a cell coming into contact with another cell). Furthermore, most cells can only replicate a finite number of times and are thus programmed to die after a certain number of cell divisions. Cancer results when a cell overcomes these built-in checkpoints and proliferates uncontrollably. This uncontrolled growth leads to tumor formation. There are two types of tumors: benign and malignant. Benign tumors are unable to cross the natural boundaries between tissue types. Malignant tumors, on the other hand, are capable of infiltrating nearby tissues or entering the bloodstream and metastasizing elsewhere. Only malignant tumors are considered cancerous. It is this ability to infiltrate and metastasize that makes cancer such a deadly disease. Furthermore, lipid metabolism may play a significant role in cancer metastasis. Cancer cells often exhibit fundamentally altered cellular metabolism. However, the role of lipid metabolism in the development of malignant tumors remains unclear. Fighting cancer is complicated by the fact that malignant tumors contain a variety of cell types. One of the most dangerous types are cancer stem cells (CSCs). CSCs are capable of self-renewal and differentiate into the various cancer cell types found within a malignant tumor. Thus, CSCs are a major contributor to tumor metastasis. CSCs often survive radiation and chemotherapy. Cancer recurrence after radiation and chemotherapy is thought to be a result of the inability of radiation and chemotherapy to kill all CSCs, combined with the ability of CSCs to form new tumors. Chemotherapy is a term used to describe a specific type of cancer treatment that involves the use of cytotoxic anticancer drugs. Cytotoxic drugs used in chemotherapy can be divided into several main categories, including alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors. Cytotoxic anticancer drugs typically stop cell division and thus affect both healthy and cancerous tissue. Alkylating agents stop cancer cell division by damaging their DNA. Some common alkylating agents used to treat cancer are nitrogen mustards (e.g., cyclophosphamide (Cytoxan®, Cytoxan is a registered trade name from Baxter International), nitrosoureas, alkyl sulfonates, triazeins, and ethyleneimines. Platinum-based drugs such as cisplatin and carboplatin act similarly to alkylating agents. Antimetabolites stop cancer cell division by inhibiting DNA and RNA synthesis. Some common antimetabolites used to treat cancer are 6-mercaptopurine, gemcitabine (Gemzar®, Gemzar is a registered trade name from Eli Lilly and Company), methotrexate, and pemetrexed (Alimta®, Alimta is a registered trade name from Eli Lilly and Company). Topoisomerase inhibitors - 1 053296 stop cancer cell division by inhibiting topoisomerase enzymes, which separate DNA for replication. Some common topoisomerase inhibitors include topotecan, irinotecan, etoposide, and teniposide. Mitotic inhibitors stop cancer cell division by inhibiting key cell division enzymes. Some common mitotic inhibitors include taxanes (e.g., paclitaxel (Taxol®, Taxol is a registered