US-12624015-B2 - JNK inhibitors as anticancer agents

US12624015B2US 12624015 B2US12624015 B2US 12624015B2US-12624015-B2

Abstract

Compounds that inhibit JNK, e.g., JNK2 and/or JNK3, such as fused thiophenes, and methods of making and using the compounds are provided.

Inventors

Aliasger K. Salem
Somaya Ali Mohammed Elsaid Abdelrahman

Assignees

UNIVERSITY OF IOWA RESEARCH FOUNDATION

Dates

Publication Date: 20260512
Application Date: 20200624

Claims (6)

1 . A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, substituted alkyl, carbocycle or heterocycle; wherein X is CONH(C1-C6) alkyl; and wherein R 1 and R 2 independently are alkyl, alkenyl, alkynyl, alkoxy, or substituted alkyl or R 1 and R 2 together form a C6 or C7 ring.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is halo, (C1-C6)alkyl, substituted (C1-C6)alkyl, or C5-C7 carbocycle.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together form a C6 ring.
4 . The compound of claim 1 which is: or a pharmaceutically acceptable salt thereof.
5 . A composition having nanoparticles comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
6 . The composition of claim 5 , wherein the nanoparticles comprise a polymer comprising lactic acid, glycolic acid, caproic acid, a polyanhydride, or a combination thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Stage Filing under 35 U.S.C. 371 from International Application No. PCT/US2020/039373, filed on Jun. 24, 2020, and published as WO 2020/263989 on Dec. 30, 2020, which application claims the benefit of the filing date of U.S. application No. 62/865,659, filed on Jun. 24, 2019, the disclosures of which are incorporated by reference herein. BACKGROUND Protein kinases, catalyzing the transfer of the terminal phosphate group of ATP to specific amino acid residues in target proteins, are the largest family of enzymes encoded by the human genome. The phosphorylation of the target protein results in modified activity, degradation, localization or association with other molecules. Among the mitogen-activated protein kinases (MAPKs) is the c-Jun N-terminal kinase (JNK) family that includes at least three proteins (JNK1, JNK2 and JNK3) that are encoded by three separate genes jnk1 (Mapk8), jnk2 (Mapk9) and jnk3 (Mapk10), and are alternatively spliced to create at least many variants. JNK1 and JNK2 are expressed in most tissues, while the expression of JNK3 is largely restricted to brain, heart and testes. JNKs regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death, and persistent activation of JNKs is involved in cancer development and progression. However, JNK1 and JNK2 may have distinct or even opposing functions in different types of cancer. Some JNK inhibitors have a lack of specificity and cellular toxicity, which is less than desirable for therapeutics. SUMMARY The disclosure provides a compound of formula (I): wherein R is hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, or substituted alkyl, alkenyl or alkynyl, or a carbocycle or heterocycle; wherein X comprises an alkyl, carbonyl, or amide; and wherein R1 and R2 independently are alkyl, alkenyl, alkynyl, alkoxy, or substituted alkyl or R1 and R2 together form a C6 or C7 ring; or a pharmaceutically acceptable salt thereof. In one embodiment, R is hydrogen, halo, (C1-C6)alkyl, or substituted (C1-C6)alkyl. In one embodiment, halo is Br, F or I. In one embodiment, R is a carbocycle, e.g., an aryl such as a C5, C6, C7, or C8 aryl. In one embodiment, R is a substituted carbocycle. In one embodiment, R is not benzyl. In one embodiment, R is not hydrogen. In one embodiment, X is (C1-C6)alkyl, CONH or CONH(C1-C6)alkyl. In one embodiment, X is substituted (C1-C6)alkyl, or substituted CONH(C1-C6)alkyl. In one embodiment, X has a chain length of no more than 6 atoms. In one embodiment, R1 and R2 together form a C7 ring. In one embodiment, R1 and R2 together form a C6 ring. In one embodiment, R1 and R2 together form an aryl ring. In one embodiment, the compound is is a benzamide. In one embodiment, the compound is a benzylamine. In one embodiment, the compound comprises urea. In one embodiment, the compound is a fused thiophene. In one embodiment, the compound inhibits JNK2 and/or JNK3. In one embodiment, the compound is not N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)1-naphthamide. In one embodiment, the X is not COCONHNCC═C(C6H5). Also provided is a composition having the compound. In one embodiment, the composition comprises nanoparticles having the compound. In one embodiment, the nanoparticles have a diameter from about 100 nm to about 250 nm. In one embodiment, the nanoparticles are formed of a synthetic polymer, e.g., lactic acid, glycolic acid, caproic acid, a polyanhydride, or a combination thereof. N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)1-naphthamide was found to be a potent JNK inhibitor with pIC50 values of 6.5 and 6.7 for JNK2 and JNK3, respectively. As disclosed herein, certain fused thiophenes, e.g., having formula (I) or (II), including those that inhibit one or more distinct JNKs, have anti-cancer activity. In one embodiment, a series of 3-cyano-4,5,6,7-tetrahydro-1-benzothiophene with 2-benzamides, 2-benzylamines or 2-urea moieties were designed as potential anticancer agents through inhibition of JNKs. In vitro anticancer screening using a MTS assay against A549 cell line showed that an exemplary benzyl urea (1), 3-bromobenzamide (2) and 4-bromobenzylamine (3) were the most active members among the ureas, benzamides and benzylamines, with IC50 values of 1.6, 7.6 and 2.7 μM, respectively. The inhibitory activity of the synthesized compounds against JNK2 and JNK3 was determined. The selective JNK inhibitors disclosed herein are useful as anticancer agents. In one embodiment, the disclosure provides for a compound of formula (I): wherein X≡CO; CH2; CONH; or CONHCH2; wherein R=2-I; 2-Br; 3-Br; 4-Br; 2-F; C10H7; C6H5; 2-BrC6H4; 4-CH3C6H4; 4-OCH3C6H4; 4-n-C4H9C6H4; or C6H5CH2. In one embodiment, X comprises alkyl, carbonyl or an amide. In one embodiment, X is CO, CH2CONH or CONHCH2. In one embodiment, R is halo, hydrogen, alkyl, e.g., C1-C10 alkyl, alkenyl, substituted alk