Hybrid cyclic libraries and screens thereof

Patent metadata

Field	Value
Publication number	US-10414801-B2
Application number	US-201715728282-A
Country	US
Kind code	B2
Filing date	Oct 9, 2017
Priority date	Nov 30, 2010
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

Provided are novel types of hybrid cyclic libraries that contain a known protein binding domain of a natural product. Also provided are synthetic methods to make such libraries and methods for the deconvolution of hits using partially split-pooled library compounds. Such methods are applicable for use with the entire human proteome to screen such libraries that bind and for the identification of hits.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof bound to one or more proteins, wherein:
is a single or double bond;
X 1 is O or NR 6 ;
Y is —C(O)— or

X 2 is (CH 2 ) m , O, or NR 6 ;
Z is

W is O, CH, CH 2 , CR 4 , or CR 5 ;
L 1 and L 2 are each independently a direct bond, substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)—, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 )NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;
each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
R 1 is

 wherein

 is a resin;
R 2 is hydrogen, hydroxyl, or alkoxy;
R 3 is hydrogen or alkyl;
R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;
R 6 is hydrogen or alkyl;
wherein the Effector Domain has Formula II:

wherein:
R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or alkyl;
R 8 , R 10 , R 12 , and R 14 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , or —(CH 2 ) n NR 19 S(O) j NR 17 R 18 ;
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
j is an integer selected from 0, 1, and 2;
R 16 , R 17 , R 18 , and R 19 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or
R 16 and R 19 are as described above, and R 17 and R 18 , together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl,
wherein each of the above groups listed for R 8 , R 10 , R 12 , and R 14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , and —(CH 2 ) n NR 19 S(O) j NR 17 R 18 .

2. The compound of Formula I of claim 1 , wherein:
X is O or NR 6 ;
L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —(CH 2 ) n O(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, —(CH 2 ) n NH(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(CH 2 ) n S(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(CH 2 ) n O(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, —(CH 2 ) n S(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
R 1 is

 wherein

 is a resin;
R 2 is hydroxyl or alkoxy;
R 3 is hydrogen or alkyl;
R 4 and R 5 are each independently hydrogen, alkyl, alkoxy, or OPG, wherein PG is a silyl protecting group;
R 6 is hydrogen;
R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or CH 3 ;
R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, or substituted or unsubstituted cyclooctyl; or
R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydrothiophenyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 1,3-dioxolanyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted 1,4-dioxanyl, substituted or un

Assignees

• Univ Johns Hopkins

Inventors

• Liu Jun O
• Wang Jingxin
• Guo Zufeng
• Li Wei
• Bhat Shridhar
• Das Manisha

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/00

  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) · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title