Novel FGFR inhibitors and uses thereof

A compound and pharmaceutical technology, applied in the field of cancer treatment, pan-FGFR and FGFR4 specific inhibitors, can solve the problem of suboptimal potency and bioavailability of BLU9931

Pending Publication Date: 2021-07-23
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the potency and bioavailability of BLU9931 are suboptimal for clinical applications

Method used

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  • Novel FGFR inhibitors and uses thereof
  • Novel FGFR inhibitors and uses thereof
  • Novel FGFR inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0075] Design of pyridylpyrimidine-based FGFR inhibitors

[0076] Using structure-based design, two pyridylpyrimidine-based FGFR inhibitors have been discovered: pan-FGFR inhibitors and FGFR4-specific inhibitors. Specifically, docking was performed to assess the binding mode and affinity of candidate inhibitors to FGFRs.

[0077] like Figure 1B As shown, FGFR4 contains a cysteine ​​(Cys552), which is located near the ATP-binding site of the receptor hinge region, unique in the FGFR family, and rare in other kinases. Covalent inhibitors of FGFR4 kinase can potently and selectively inhibit FGFR by covalently targeting the thiol (SH) group in cysteine ​​residues ( Figure 1A ).

[0078] Structure-based design approaches have enabled the discovery of novel pan-FGFR inhibitors, such as Figure 2A Compound 1 and FGFR4 specific inhibitors shown in, such as Figure 2B Compounds 2, 3 and 4 shown in .

example 2

[0080] General structure of novel FGFR4-specific inhibitors

[0081] Using the structure-based design described above, general structures for other FGFR4-specific inhibitors were established. Other FGFR4-specific inhibitors can be synthesized with general structures such as image 3 shown.

[0082] In the general structure above, X is CH or N. In the top benzene ring, each R 1 Substituents are hydrogen, halogen or methoxy, and n is 0-4. In the second benzene ring, each R 2 Substituents are hydrogen, methyl, amino, or propargyloxy, and n is 1-2. The phenyl group contains a warhead, which is usually attached to an N atom and is an electrophilic moiety that can form a covalent bond with a nucleophile. Examples of warheads include, but are not limited to, haloacetamides and acrylamides.

example 3

[0084] In vitro efficacy evaluation of FGFR inhibitors

[0085] The efficacy of compounds to inhibit FGFR kinase activity was measured by determining IC50 values.

[0086] Two of the compounds were tested in vitro against the corresponding FGFRs: Compound 1 and Compound 2 (FGFR2 for Compound 1 pan-inhibitor and FGFR4 for Compound 2 covalent inhibitor). The results are listed in Table 4, expressed as IC 50 value (concentration of compound that inhibits 50% of enzymatic activity).

[0087] Table 4. In vitro inhibition assays for compounds 1 and 2

[0088]

[0089] To assess the efficacy profile of compounds to inhibit enzymatic activity, compounds 1 and 2 were evaluated for their inhibition of 15 different kinases. As shown in Table 5, Compound 1, a pan-FGFR inhibitor, showed significant inhibition of all members of the FGFR family, as well as some inhibitory activity against some other kinases. Compound 2 showed high selectivity and potency for FGFR4 (only selected dat...

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Abstract

The invention provides novel FGFR inhibitors based on the pyridinylpyrimidine. The invention includes inhibitors with broad inhibitory activity against all FGFR isoforms, and inhibitors with selective inhibition against FGFR4. These novel pyridinylpyrimidine-based FGFR inhibitors, or their derivatives, have strong potential to be used to treat cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority under 35 U.S.C. § 119(e) to US Serial No. 62 / 730,921, filed September 13, 2018, the entire contents of which are incorporated herein by reference in their entirety. [0003] Merged Sequence Listing [0004] The material in the appended Sequence Listing is hereby incorporated by reference into this application. The attached sequence listing text file is named USC1280_1WO_Sequence_Listing.txt, was created on September 11, 2019, and is 1,084kb in size. The file can be accessed using Microsoft Word on a computer with a Windows operating system. technical field [0005] The present invention relates generally to novel fibroblast growth factor receptor (FGFR) inhibitors, and more particularly to the use of pyridylpyrimidine-based pan-FGFR and FGFR4 specific inhibitors for the treatment of cancer. Background technique [0006] The human fibroblast growth factor receptor (FGFR) family consist...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506C07D239/42C07D403/04
CPCC07D401/04A61K45/06
Inventor 张超R·R·米兰达倪锋J·卡普滕
Owner UNIV OF SOUTHERN CALIFORNIA
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