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US-12624109-B2 - αv-integrin targeted small molecule drug conjugates

US12624109B2US 12624109 B2US12624109 B2US 12624109B2US-12624109-B2

Abstract

A chemical compound and a method for treating cancer in a mammal. The chemical compound is a first Markusch structure of A-L 1 -PEG 1 -L 2 -PEG 2 -CL-X, a second Markusch structure of A-L 1 -PEG 1 -N 3 , or a third Markusch structure of A-L 1 -PEG 1 -OMethyl. A-L 1 -PEG is a targeting structure configured for targeting av integrins in cancer cells and does not include a standard multivalent nitrogen moiety. A is a structure that includes a standard carboxylic acid moiety. L 1 and L 2 are linking structures. PEG 1 and PEG 2 are polyethylene glycol structures having n 2 and n 4 monomer units, respectively, where n 2 is in range of 5-72, n 4 is in range of 0-67, and n 2 +n 4 is in range of 20-72. CL is a cleavage linker linked to PEG 2 . X is a chemotherapy linked to CL. N 3 is —N═N═N. In one embodiment, the method uses the first Markusch structure to treat the cancer.

Inventors

  • Shaker A. Mousa
  • Bruce A. Hay

Assignees

  • TARGETTHERA LLC

Dates

Publication Date
20260512
Application Date
20230425

Claims (20)

  1. 1 . A chemical compound comprising the following Markush structure: A-L 1 -PEG 1 -L 2 -PEG 2 -CL-X wherein A-L 1 -PEG 1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein L 1 is a first linking structure selected from the group consisting of and NULL; wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein L 2 is the following second linker structure, wherein n 3 is in a range of 0-4: wherein PEG 2 is the following polyethylene glycol repeating structure, wherein n 4 is in a range of 0-67 and n 2 +n 4 is in a range of 20-72: wherein CL is a cleavable linker; and wherein X is either Chemo1 or L 3 -Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L 3 is the following linker that links Chemo2 to CL: wherein wherein n 1 is in a range of 1-6; wherein Ar is selected from the group consisting of wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl; wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; and wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.
  2. 2 . The chemical compound of claim 1 , wherein n 4 is in a range of 0-43 and n 2 +n 4 is in a range of 20-48.
  3. 3 . The chemical compound of claim 1 , wherein n 4 =0.
  4. 4 . The chemical compound of claim 1 , wherein X is Chemo1.
  5. 5 . The chemical compound of claim 1 , wherein X is L 3 -Chemo2.
  6. 6 . The chemical compound of claim 1 , wherein L 1 is NULL.
  7. 7 . The chemical compound of claim 1 , wherein L 1 is selected from the group consisting of
  8. 8 . The chemical compound of claim 1 , wherein the chemical compound is
  9. 9 . A chemical compound, comprising the following Markush structure: A-L 1 -PEG 1 -L 2 -PEG2-CL-X wherein A-L 1 -PEG 1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein L 1 is a first linking structure selected from the group consisting of and NULL; wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein L 2 is the following second linker structure, wherein n 3 is in a range of 0-4: wherein PEG 2 is the following polyethylene glycol repeating structure, wherein n 4 is in a range of 0-67 and n 2 +n 4 is in a range of 20-72: wherein CL is a cleavable linker; and wherein X is either Chemo1 or L 3 -Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L 3 is the following linker that links Chemo2 to CL: wherein and wherein Ar is selected from the group consisting of wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl; wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; and wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.
  10. 10 . The chemical compound of claim 9 , wherein the chemical compound is
  11. 11 . A chemical compound, comprising the following Markush structure: A-L 1 -PEG 1 -L 2 -PEG 2 -CL-X wherein A-L 1 -PEG 1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein L 1 is a first linking structure selected from the group consisting of and NULL; wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein L 2 is the following second linker structure, wherein n 3 is in a range of 0-4: wherein PEG 2 is the following polyethylene glycol repeating structure, wherein 114 is in a range of 0-67 and n 2 +n 4 is in a range of 20-72: wherein CL is a cleavable linker; and wherein X is either Chemo1 or L 3 -Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L 3 is the following linker that links Chemo2 to CL: wherein and wherein R4 is selected from the group consisting of hydrogen, Alkyl, and Ar; wherein Alkyl is selected from the group consisting of Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; wherein Ar is selected from the group consisting of wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl; wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; and wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.
  12. 12 . The chemical compound of claim 11 , wherein the chemical compound is
  13. 13 . A chemical compound, comprising the following Markush structure: A-L 1 -PEG 1 -N 3 wherein A-L 1 -PEG 1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein L 1 is a first linking structure selected from the group consisting of; and wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein wherein n 1 is in a range of 1-6; wherein Ar is selected from the group consisting of: wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl, wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; and wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.
  14. 14 . The chemical compound of claim 13 , wherein the chemical compound is
  15. 15 . A chemical compound, comprising the following Markush structure: A-L 1 -PEG 1 -OMethyl wherein A-L 1 -PEG 1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein L 1 is a first linking structure selected from the group consisting of and NULL; wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein wherein n 1 is in a range of 1-6: wherein Ar is selected from the group consisting of wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl; and wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.
  16. 16 . The chemical compound of claim 15 , wherein n 2 is in a range of 20-48.
  17. 17 . The chemical compound of claim 15 , wherein L 1 is NULL.
  18. 18 . The chemical compound of claim 15 , wherein L 1 is selected from the group consisting of
  19. 19 . The chemical compound of claim 15 , wherein the chemical compound is
  20. 20 . A method for treating cancer in a mammal, said method comprising: administering a therapeutically effective amount of a chemical compound to the mammal; wherein αv integrins are overexpressed in tumors comprising cancer cells of the cancer in the mammal; said chemical compound comprising the following Markush structure: A-L 1 -PEG 1 -L 2 -PEG 2 -CL-X wherein A-L 1 -PEG 1 is a targeting structure configured for targeting the αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety; wherein A is a structure that includes a standard carboxylic acid moiety; wherein wherein n 1 is in a range of 1-6; wherein Ar is selected from the group consisting of wherein R 5 -R 11 are each independently selected from the group consisting of: H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF 3 , —OCF 3 , —CHF 2 , —OCHF 2 , —SO 2 Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl; wherein Alkyl is selected from the group consisting of: Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C 5 -C 12 n-alkyl, cyclopentyl, and cyclohexyl; wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl; wherein L 1 is a first linking structure selected from the group consisting of wherein PEG 1 is the following polyethylene glycol structure, wherein n 2 is in a range of 5-72: wherein L 2 is the following second linker structure, wherein n 3 is in a range of 0-4: wherein PEG 2 is the following polyethylene glycol repeating structure, wherein n 4 is in a range of 0-67 and n 2 +n 4 is in a range of 20-72: Wherein CL is a cleavable linker; and wherein X is either Chemo1 or L 3 -Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L 3 is the following linker that links Chemo2 to CL:

Description

BACKGROUND Antibody-drug-conjugates (ADCs) are an important new class of anti-cancer drugs, with at least 12 approved by the FDA, and many more undergoing clinical trials (recently reviewed in Fu, Signal Transduct Target Ther 7, 2022). These ADC molecules target cancer cells, where most of these molecules release a chemotherapy inside tumor cells, which can result in a big improvement in therapeutic index for the chemotherapy, since systemic toxicity is reduced because of less systemic exposure to the chemotherapy. ADCs typically have high selectivity for tumor cells with good in vivo stability. The mechanism for release of chemotherapy for most ADCs requires the ADC to be internalized into the cell, eventually ending up in a cell organelle called the late endosome, or in a cell organelle called the lysosome. After being internalized inside the tumor cell, the chemotherapy is cleaved from the ADC via a specific enzyme (cathepsin B) that is active in these organelles (i.e., late endosome and/or lysosome). One issue with ADCs is that typically only a very small fraction (<1%) of the dosed ADC enters the tumor, some of which is believed to be due at least partially to ineffective transport of the macromolecular ADC to the tumor site (Tong, Molecules 2021, 26, 5847). Another issue with ADCs is the internalization efficiency varies with different ADCs, and is usually suboptimal (Hammood, Pharmaceuticals 2021, 14, 674). In addition, ADCs are an expensive therapy that needs to be dosed via IV infusion, with each infusion requiring a visit to the doctor's office. There are a number of reports on Small Molecule Drug Conjugates (SMDCs) using integrin αvβ3 targeting. The vast majority of these SMDCs use Arginylglycylaspartic acid (RGD) peptide or related peptides as the targeting agent, but there are a few SMDCs that use peptidomimetics. A peptidomimetic is a small protein-like chain designed to mimic a peptide. The reported peptidomimetics mimic the RGD peptide by using the standard formula of an acidic functionality and a standard multivalent nitrogen moiety spaced 12-14 angstroms apart. The standard multivalent nitrogen (hereinafter, “multivalent nitrogen”), whose scope includes multivalent nitrogen moieties illustrated infra, is defined as a chemical substructure with at least 2 nitrogen atoms connected by a single atom, that mimics the guanidine in the arginine of the Arginylglycylaspartic acid (RGD) peptide, where guanidine has the following chemical structure: The multivalent nitrogen moiety is illustrated by the following Guanidine, Amidine, 2-aminopyridine, Urea, 1,2,3-triazole type structures: Attached chemotherapies include Doxorubicin, paclitaxel, camptothecins, monomethylauristatin, cisplatin, etc. There are several recent literature reviews on SMDCs (Cirillo et al, cancers 2021, 13, 299 and Battistini et al, Eur. J. Org. Chem. 2021, 2506-2528) as well as some earlier reviews (Dal Corso et al, current topics in medicinal chemistry, 2016, 16, 314-329). The abstract of the 2016 Dal Corso et al review recites “Despite the significant efforts made in this field, integrin αvβ3 integrin-targeted SMDCs are still far from the clinic.” Huthchinson, J. Med Chem 2003, 46, 4790 discloses MK-0429 (shown infra) which has the basic multivalent nitrogen 12-14 angstroms from carboxylic acid. Carboxylic acid has the following chemical structure: —C(═O)OH. Some specific references of interest on RGD targeted SMDCs include (Dias et al ChemMedChem 2019, 14, 938-942), with RGD peptide targeting the chemotherapy of monomethylauristatin, that use cleavable linker Val-Cit-PAB (VCP), connected to a small polyethylene glycol (PEG) (i.e., PEG3). PEG3 is PEG having 3 monomer units. This VCP linker is also used in an RGD peptide targeted paclitaxel (Zanella et al, Chem. Eur. J. 2017 23 7910-14). Val-Cit-PAB (VCP) and similar cathepsin B cleavable linkers, as well as chemotherapy monomethylauristatin E (MMAE), have been used extensively in ADCs for the last 20 years. For early references, see Doronina 2003 Nature Biotechnology 2003, 21, 778-784 and the patent WO 03/043583 with a filing date of 20 Nov. 2002. The Val-Cit-PAB and related cleavable linkers need a chemotherapy with a primary or preferably a secondary amine functionality to attach the cleavable linker to the chemotherapy. There are also a few references for integrin αvβ3 peptidomimetic targeting of SMDCs, which use the “standard” integrin αvβ3 peptidomimetic that has the acidic group and the multivalent nitrogen group 12-14 angstroms apart, including the following compound from WO2022094471 which has a PEG3 linker. There are no PEG linkers in integrin avb3 targeted small molecule drug conjugates longer than PEG15 disclosed or claimed in the literature or patents. The preceding compound has a peptidomimetic integrin αvβ3 targeting piece that contains a multivalent nitrogen of about 12-14 angstroms from the carboxylic acid functionality, as in the RGD peptide. There are actual