# US 12,214,047 B2 · FAP-activated proteasome inhibitors for treating solid tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,214,047 B2 - Document ID: US12214047B2 - Status: Granted - Kind: B2 - Application number: 17/348,043 - Filed: 2021-06-15 - Published: 2021-12-09 - Granted: 2025-02-04 - Earliest claimed: 2011-08-30 - Assignees: Trustees of Tufts College - Applicants: Trustees of Tufts College - Inventors: William W. Bachovchin; Hung-sen Lai; Sarah E. Poplawski - Web page: https://patentgrep.com/patent/US12214047B2 ## CPC - A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) - A61K 31/69: Boron compounds - A61K 38/07: Tetrapeptides - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 47/54: the modifying agent being an organic compound - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 17/06: Antipsoriatics - A61P 35/00: Antineoplastic agents - C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala} - C07K 5/06034: {the side chain containing 2 to 4 carbon atoms} - C07K 5/06078: {and aromatic or cycloaliphatic} - C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala} - C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu} - C07K 5/081: {the side chain containing O or S as heteroatoms, e.g. Cys, Ser} - C07K 5/0812: {and aromatic or cycloaliphatic} - C07K 5/0821: {with the first amino acid being heterocyclic, e.g. His, Pro, Trp} - C07K 5/1016: {and aromatic or cycloaliphatic} - G01N 33/575: for cancer - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Disclosed are proteasome inhibitors, fibroblast activation protein (FAP)-activated prodrugs of proteasome inhibitors, and pharmaceutically acceptable salts of the inhibitors and prodrugs. Also disclosed are related pharmaceutical compositions, and methods of using the inhibitors and prodrugs and compositions thereof, for example, in treating cancer or other cell proliferative diseases. In vitro and in vivo methods of quantifying the expression of FAP in a biopsy sample and a mammal, respectively, are also disclosed. ## Claims ### Claim 1 A FAP-activated prodrug of a proteasome inhibitor represented by formula I: A-B I or a pharmaceutically acceptable salt thereof, wherein A is Ser-(d)-Ala-Pro or (blocking group)-Ser-(d)-Ala-Pro, wherein the N-terminus of Ser is substituted with the blocking group; B is A and B being covalently linked by a bond that is enzymatically cleaved by FAP to release B in the free form; and the prodrug has a kcat/Km for FAP cleavage of the bond linking A and B of at least 10 fold more than for Prolyl endopeptidase EC 3.4.14.5 (PREP). ### Claim 2 (depends on 1) The FAP-activated prodrug of claim 1, wherein A is (blocking group)-Ser-(d)-Ala-Pro, wherein the N-terminus of Ser is substituted with the blocking group. ### Claim 3 (depends on 2) The FAP-activated prodrug of claim 2, wherein the blocking group is a (lower alkyl)-C(═O)' substituted with one or more functional groups that are ionized at physiological pH. ### Claim 4 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 5 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 6 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 7 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 8 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 9 (depends on 1) The FAP-activated prodrug of claim 1, wherein B is ### Claim 10 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 11 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 12 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 13 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 14 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 15 (depends on 2) The FAP-activated prodrug of claim 2, wherein B is ### Claim 16 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is ### Claim 17 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is ### Claim 18 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is ### Claim 19 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is ### Claim 20 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is ### Claim 21 (depends on 3) The FAP-activated prodrug of claim 3, wherein B is