Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors

被引：6

作者：

Caldwell, Timothy M. ^{[1
]}

Kaufman, Michael D. ^{[1
]}

Wise, Scott C. ^{[1
]}

Ahn, Yu Mi ^{[1
]}

Hood, Molly M. ^{[1
]}

Lu, Wei -Ping ^{[1
]}

Patt, William C. ^{[1
]}

Samarakoon, Thiwanka ^{[1
]}

Vogeti, Lakshminarayana ^{[1
]}

Vogeti, Subha ^{[1
]}

Yates, Karen M. ^{[1
]}

Bulfer, Stacie L. ^{[1
]}

Le Bourdonnec, Bertrand ^{[1
]}

Smith, Bryan D. ^{[1
]}

Flynn, Daniel L. ^{[1
,2
]}

机构：

[1] Deciphera Pharmaceut LLC, Waltham, MA 02451 USA

[2] 643 Massachusetts St,Suite 200, Lawrence, KS 66044 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 74卷

关键词：

CSF1R; Kinase; Acyl ureas; Cancer; TUMOR-ASSOCIATED MACROPHAGES; STIMULATING FACTOR-I; MICROGLIAL PROLIFERATION;

D O I：

10.1016/j.bmcl.2022.128929

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified dis-playing high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-alpha, PDGFR-beta, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.

引用

页数：6

共 24 条

[21] Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial [J].

Tap, William D. ;

Gelderblom, Hans ;

Palmerini, Emanuela ;

Desai, Jayesh ;

Bauer, Sebastian ;

Blay, Jean-Yves ;

Alcindor, Thierry ;

Ganjoo, Kristen ;

Martin-Broto, Javier ;

Ryan, Christopher W. ;

Thomas, David M. ;

Peterfy, Charles ;

Healey, John H. ;

van de Sande, Michiel ;

Gelhorn, Heather L. ;

Shuster, Dale E. ;

Wang, Qiang ;

Yver, Antoine ;

Hsu, Henry H. ;

Lin, Paul S. ;

Tong-Starksen, Sandra ;

Stacchiotti, Silvia ;

Wagner, Andrew J. .

LANCET, 2019, 394 (10197) :478-487

[22] Protein kinases: evolution of dynamic regulatory proteins [J].

Taylor, Susan S. ;

Kornev, Alexandr P. .

TRENDS IN BIOCHEMICAL SCIENCES, 2011, 36 (02) :65-77

[23] A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells [J].

West, RB ;

Rubin, BP ;

Miller, MA ;

Subramanian, S ;

Kaygusuz, G ;

Montgomery, K ;

Zhu, S ;

Marinelli, RJ ;

De Luca, A ;

Downs-Kelly, E ;

Goldblum, JR ;

Corless, CL ;

Brown, PO ;

Gilks, CB ;

Nielsen, TO ;

Huntsman, D ;

van de Rijn, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (03) :690-695

[24] Small-Molecule CSF1R Inhibitors as Anticancer Agents [J].

Xun, Qiuju ;

Wang, Zhen ;

Hu, Xianglong ;

Ding, Ke ;

Lu, Xiaoyun .

CURRENT MEDICINAL CHEMISTRY, 2020, 27 (23) :3944-3966

← 1 2 3 →