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editorial
. 2020 Oct 1;11(12):2346–2347. doi: 10.1021/acsmedchemlett.0c00500

Novel CDK2 Inhibitors for Treating Cancer

Ram W Sabnis 1,*
PMCID: PMC7734635  PMID: 33335646

Important Compound Classes

graphic file with name ml0c00500_0001.jpg

Title

CDK2 Inhibitors

Patent Publication Number

WO 2020/157652 A2

Publication Date

August 6, 2020

Priority Application

US 62/799,455 and US 62/959,042

Priority Date

January 31, 2019 and January 9, 2020

Inventors

Behenna, D. C.; Freeman-Cook, K. D.; Hoffman, R. L.; Nagata, A.; Ninkovic, S.; Sutton, S. C.

Assignee Company

Pfizer Inc., USA

Disease Area

Cancer

Biological Target

CDK2

Summary

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDKs 1–4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression, while CDKs 3, 5, and 7–9 may play an indirect role. The CDK catalytic units are activated by binding to regulatory subunits, known as cyclins, followed by phosphorylation. Cyclins can be divided into four general classes (G1, G1/S, S, and M cyclins) whose expression levels vary at different points in the cell cycle.

Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Cyclin E amplification or overexpression has long been associated with poor outcomes in breast cancer. Amplification or overexpression of cyclin E1 (CCNE1) is associated with poor outcomes in ovarian, gastric, endometrial, and other cancers.

The small molecule inhibitor dinaciclib inhibits CDK1, CDK2, CDK5, and CDK9 and is currently in clinical development for breast and hematological cancers. Seliciclib, which inhibits CDK2, CDK7, and CDK9 was studied in nasopharyngeal cancer. CYCO65, which inhibits CDK2 and CDK9, is in early clinical development. Despite significant efforts, there are no approved agents selectively targeting CDK2 to date. The present application describes a series of novel CDK2 inhibitors that are useful for treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R1 = -L1-(5–10 membered heteroaryl) or -L1-(C6–C12 aryl), where 5–10 membered heteroaryl or C6–C12 aryl is optionally substituted by one or more R4;

R2 and R3 are independently H, C1–C6 alkyl, C1–C6 fluoroalkyl, -L2-(C3–C7 cycloalkyl) or -L2-(4–7 membered heterocyclyl), where each C1–C6 alkyl and C1–C6 fluoroalkyl is optionally substituted by one or more R5 and C3–C7 cycloalkyl and 4–7 membered heterocyclyl is optionally substituted by one or more R6; or

R2 and R3 are taken together with the N atom to which they are attached to form a 4–6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R7), and S(O)q as a ring member, where 4–6 membered heterocyclyl is optionally substituted by one or more R8;

L1 and L2 is independently a bond or a C1–C2 alkylene optionally substituted by one or more R9;

R4 = F, Cl, OH, CN, NR10R11, C1–C4 alkyl, C1–C4 fluoroalkyl, C1–C4 alkoxy, C1–C4 fluoroalkoxy, C3–C8 cycloalkyl, C(O)NR10R11, SO2R12, SO(=NH)R12 or SO2NR10R11, where each C1–C4 alkyl and C1–C4 fluoroalkyl is optionally substituted by one or more R13;

R5 = OH, C1–C4 alkoxy or NR10R11;

R6 = F, OH, C1–C4 alkyl, C1–C4 fluoroalkyl, C1–C4 alkoxy, C1–C4 fluoroalkoxy or NR10R11 where each C1–C4 alkyl, C1–C4 fluoroalkyl is optionally substituted by one or more R13;

R7 = H, C1–C4 alkyl or C(O)-C1–C4 alkyl;

R8 = F, OH, C1–C4 alkyl, C1–C4 alkoxy or CN;

R9 = F, OH, or C1–C2 alkyl;

R10 and R11 are independently H, or C1–C2 alkyl;

R12 = C1–C4 alkyl or C3–C6 cycloalkyl;

R13 = OH, C1–C4 alkoxy or NR14R15;

R14 and R15 are independently H, or C1–C2 alkyl; and

q = 0, 1 or 2.

Key Structures

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Biological Assay

The CDK2/cyclin E1 and GSK3β assays were performed. The compounds described in this application were tested using a fluorescence-based microfluidic mobility shift assays to test the ability of the compounds to inhibit CDK2/cyclin E1 and GSK3β. The CDK2/cyclin E1 Ki (nM) and GSK3β Ki (nM) inhibition are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for CDK2/cyclin E1 and GSK3β inhibition. The biological data obtained from testing representative examples are listed in the following table.graphic file with name ml0c00500_0003.jpg

Claims

Total claims: 20

Compound claims: 18

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Recent Review Articles

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    Tadesse S.; Anshabo A. T.; Portman L.; Lim E.; Tilley W.; Caldon C. E.; Wang S.. Drug Discovery Today 2020, 25, 406.

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    Leal-Esteban L. C.; Fajas L.. Biochim. Biophys. Acta, Mol. Basis Dis. 2020, 1866, 165715.

The author declares no competing financial interest.


Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

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