Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

被引：7

作者：

Black, W. Cameron ^{[1
]}

Abdoli, Abbas ^{[2
]}

An, Xiuli ^{[3
]}

Auger, Anick ^{[4
]}

Beaulieu, Patrick ^{[5
]}

Bernatchez, Michel ^{[5
]}

Caron, Cathy ^{[1
]}

Chefson, Amandine ^{[4
]}

Crane, Sheldon ^{[2
]}

Diallo, Mohamed ^{[1
]}

Dorich, Stephane ^{[4
]}

Fader, Lee D. ^{[4
]}

Ferraro, Gino B. ^{[1
]}

Fournier, Sara ^{[1
]}

Gao, Qi ^{[6
]}

Ginzburg, Yelena ^{[7
]}

Hamel, Martine ^{[1
]}

Han, Yongshuai ^{[3
]}

Jones, Paul ^{[2
]}

Lanoix, Stephanie ^{[2
]}

Lacbay, Cyrus M. ^{[2
]}

Leclaire, Marie-Eve ^{[1
]}

Levy, Maayan ^{[7
]}

Mamane, Yael ^{[1
]}

Mulani, Amina ^{[2
]}

Papp, Robert ^{[1
]}

Pellerin, Charles ^{[4
]}

Picard, Audrey ^{[4
]}

Skeldon, Alexander ^{[4
]}

Skorey, Kathryn ^{[2
]}

Stocco, Rino ^{[1
]}

St.-Onge, Miguel ^{[4
]}

Truchon, Jean-Francois ^{[1
]}

Truong, Vouy Linh ^{[2
]}

Zimmermann, Michal ^{[1
]}

Zinda, Michael ^{[1
]}

Roulston, Anne ^{[1
]}

机构：

[1] Repare Therapeut Inc, St Laurent, PQ H4S 2A1, Canada

[2] Nuchem Sci Inc, St Laurent, PQ H4R 2N6, Canada

[3] New York Blood Ctr Enterprises, New York, NY 10065 USA

[4] Ventus Therapeut Inc, St Laurent, PQ H4S 2A1, Canada

[5] OmegaChem, Levis, PQ G6W 7V6, Canada

[6] J Star Res Inc, South Plainfield, NJ 07080 USA

[7] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 04期

关键词：

ESSENTIAL KINASE; IN-VIVO; PARP; COMBINATION; MONOTHERAPY; CHLORIDE; MICE;

D O I：

10.1021/acs.jmedchem.3c01917

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

引用

页码：2349 / 2368

页数：20

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