Modified cytotoxins and their therapeutic use

Patent metadata

Field	Value
Publication number	US-10654864-B2
Application number	US-201815945285-A
Country	US
Kind code	B2
Filing date	Apr 4, 2018
Priority date	Sep 22, 2015
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

The present disclosure generally provides compounds useful for treating cancer. In some aspects, the disclosure provides small-molecule cytotoxins that are chemically modified to include one or more moieties that include hydrophobic portions. In some embodiments, the disclosure provides small-molecule cytotoxins that are chemically modified with fatty acid-containing moieties. In some aspects, the disclosure provides compositions, such as pharmaceutical compositions, that include such modified small-molecule cytotoxins and a protein. In some embodiments, the protein is albumin or an albumin mimetic. Further, the disclosure provides various uses of these compounds and compositions.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising:
a first compound, which is a compound of formula (I)
A 1 -X 1 X— 2 -A 2   (I)

wherein:
A 2 is a cytotoxic drug moiety, which has a molecular weight of no more than 1600 Da, wherein the cytotoxic drug moiety comprises an oxygen atom or an NH group through which it connects to —X 2 —X 1 -A 1 ; and
—X 2 —X 1 -A 1 is selected from the group consisting of: —C(═O)—(CH 2 ) n1 —C(═O)—OH; —C(═O)—(CH 2 ) n1 —C(═O)—OCH 3 ; —C(═O)—(C 1-6 alkylene)-C(═O)—O—(CH 2 ) n2 —C(═O)—OH; —C(═O)—(C 1-6 alkylene)-NH—C(═O)—(CH 2 ) n1 —C(═O)—OH; and —C(═O)—(C 1-6 alkylene)-C(═O)—O—[(CH 2 ) 2 —O-] n3 (CH 2 ) n2 —C(═O)—OH; wherein n1 is an integer 12 to 24, n2 is an integer from 13 to 25, and n3 is an integer from 1 to 25; and
a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 80% equivalent to that of human serum albumin.

2. The pharmaceutical composition of claim 1 , wherein the protein is human serum albumin.

3. The pharmaceutical composition of claim 1 , further comprising a carrier.

4. The pharmaceutical composition of claim 3 , wherein the carrier comprises water.

5. The pharmaceutical composition of claim 4 , wherein the compound and the protein are non-covalently associated with each other with a binding constant (K b ) of at least 10 2 M −1 .

6. The pharmaceutical composition of claim 3 , wherein the compound and the protein are solvated by the carrier.

7. The pharmaceutical composition of claim 3 , which contains one or more first compounds and one or more proteins, wherein at least 90% by weight of the compounds in the composition are bound to proteins with a binding constant (K b ) of at least 10 2 M −1 .

8. The pharmaceutical composition of claim 7 , wherein at least 90% by weight of the protein-bound particles in the composition have a radius no greater than 5 nm, as measured by dynamic light scattering.

9. A method of treating cancer, comprising:
administering to a subject a composition of claim 1 .

10. The pharmaceutical composition of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—OH; —(C═O)—(C 1-6 alkylene)-C(═O)—O—(CH 2 ) n2 —C(═O)—OH; —(C═O)—(C 1-6 alkylene)-NH—C(═O)—(CH 2 ) n1 —C(═O)—OH; or —(C═O)—(C 1-6 alkylene)-C(═O)—O—[(CH 2 ) 2 —O—] n3 —(CH 2 ) n2 —C(═O)—OH.

11. The pharmaceutical composition of claim 1 , wherein the cytotoxic drug moiety has a molecular weight of no more than 1500 Da.

12. The pharmaceutical composition of claim 1 , wherein the cytotoxic drug moiety is an organic moiety.

13. The pharmaceutical composition of claim 1 , wherein n1 or n2 is 16.

Assignees

• Univ California
• Vybyl Holdings Inc
• Elevance Renewable Sciences

Inventors

• Callmann Cassandra E
• Thompson Matthew P
• Gianneschi Nathan C
• Leguyader Clare L M
• Bertin Paul A

Classifications

• C07D475/08

  with a nitrogen atom directly attached in position 2 · CPC title

• C07D491/044 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C07H15/252

  Naphthacene radicals, e.g. daunomycins, adriamycins · CPC title

• C07D305/14 Primary

  condensed with carbocyclic rings or ring systems · CPC title