Lzk-targeting degraders and methods of use
AssigneeThe U.S.A., as represented by the Secretary, Department of Health and Human Services
InventorsJohn F. Brognard, Rolf E. Swenson, Amy L. Funk, Carolyn W. Hitko, Katherine M. Nyswaner, Eric Lindberg, Venkatareddy Sabbasani, Knickole L. Bergman
Life of this patent
Estimating the term…
Abstract
Leucine zipper-bearing kinase (LZK) targeted degraders are disclosed. The compounds have a general formula Q-L-Z where Q is an LZK binding moiety, L is a linker, and Z is an E3-ligase binding moiety. The compounds inhibit LZK activity and/or degrade LZK. The compounds may be used to treat diseases or conditions characterized at least in part by LZK overexpression.
Claims22
A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having a general formula:
- where Q is a leucine zipper kinase (LZK) binding moiety;
- Z is an E3-ligase binding moiety;
- and
- L is a linker having a general formula
- or L is absent, wherein
- L1 is —C(O)—, —S(O)2—, —CH2—, —C(Rb)(Rc)—, —(CH2)nC(O)—, —C(O)—(CH2)n—, —N(Rc)—, —N(Rc)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Rc)—, and L1 binds to Q, or L1 is absent and L2 binds to Q;
- L3 is —C(O)—, —S(O)2—, —CH2—, —C(Rb)(Rc)—, —C(O)—(CH2)n—, —(CH2)n—C(O)—, —N(Rc)—, —N(Rc)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Rc)—, and -L3 binds to Z, or L3 is absent and L2 binds to Z;
- L2 is —(Rd)p—, —N(Rb)—(Rd)p—, —(Rd)p—N(Rb)—, —N(Rb)—(Rd)p—N(Rb)—, —(N(Rb)—(C(H)(Ra))s—C(O))m—N(Rb)—C(H)(Ra)—, or —C(H)(Ra)—N(Rb)—(C(O)—(C(H)(Ra))s—N(Rb)—
- each Ra independently is an amino acid side chain;
- each Rb independently is H or Rc;
- each Rc independently is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted alkylaryl;
- each Rd independently is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH2—CH2—O)r—, —(C(H)(Ra))s—C(O)—, —C(O)N(Rb)—, or —N(Rb)C(O)—;
- each Rc independently is substituted or unsubstituted C1-C3 alkyl or H;
- m is an integer from 0-11;
- n is an integer from 1-10;
- p is an integer from 0-5;
- r is an integer from 2-20;
- and
- s is an integer from 1-20,
- wherein (i) L2 is not solely —C(O)N(Rb)— or —N(Rb)C(O)—, (ii) if L2 terminates in —C(H)(Ra)—C(O)— or —N(Rb)C(O)—, then L3 is not —C(O)— or —S(O)2—, and (iii) if L3 is absent, L2 is —(Rd)p— and p is 0, then L1 binds directly to Z,
- with the proviso that
- (i) Q is not foretinib, or
- (ii) L1 is —C(O)—, —S(O)2—, —C(Rb)(Rc)—, —(CH2)nC(O)—, —C(O)—(CH2)n—, —N(Rc)—, —N(Rc)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Rc)—, or
- (iii) L2 is other than —(Rd)p— where p is 1 and Rd is heteroaliphatic, or
- (iv) L3 is —S(O)2—, —C(Rb)(Rc)—, —C(O)—(CH2)n—, —N(Rc)—, —N(Rc)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Rc)—.
Dependencies are inferred from the claim text.