DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome.,ACS Chemical Biology

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DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-12-16 , DOI: 10.1021/acschembio.8b00866
Hans Richter ₁ , Alexander L Satz ₁ , Marc Bedoucha ₁ , Bernd Buettelmann ₁ , Ann C Petersen ₁ , Anja Harmeier ₁ , Ricardo Hermosilla ₁ , Remo Hochstrasser ₁ , Dominique Burger ₁ , Bernard Gsell ₁ , Rodolfo Gasser ₁ , Sylwia Huber ₁ , Melanie N Hug ₁ , Buelent Kocer ₁ , Bernd Kuhn ₁ , Martin Ritter ₁ , Markus G Rudolph ₁ , Franziska Weibel _{1,

2} , Judith Molina-David _{3,

4} , Jin-Ju Kim _{3,

4} , Javier Varona Santos _{3,

4} , Martine Stihle ₁ , Guy J Georges ₅ , R Daniel Bonfil ₆ , Rafael Fridman ₇ , Sabine Uhles ₁ , Solange Moll ₈ , Christian Faul ₉ , Alessia Fornoni ₃ , Marco Prunotto _{1,

10}

Affiliation

Roche Pharma Research and Early Development, Roche Innovation Center , Basel 4070 , Switzerland.
Ridgeline Therapeutics GmbH , Basel 4070 , Switzerland.
Katz Family Division of Nephrology and Hypertension , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States.
Peggy and Harold Katz Family Drug Discovery Center , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States.
Roche Pharma Research and Early Development, Roche Innovation Center , Munich 82377 , Germany.
Department of Pathology, College of Medical Sciences , Nova Southeastern University , Fort Lauderdale , Florida 33328 , United States.
Department of Pathology , Wayne State University , Detroit , Michigan 48202 , United States.
University Hospital of Geneva , 1205 Geneva , Switzerland.
University of Alabama at Birmingham , Birmingham , Alabama 35294, United States.
Office of Innovation, Immunology, Infectious Diseases & Ophthalmology (I2O) , Roche and Genentech Late Stage Development , Basel 4070 , Switzerland.

The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.

中文翻译：

DNA编码的库衍生的DDR1抑制剂可防止Alport综合征的遗传小鼠模型中的纤维化和肾功能丧失。

通过基因敲除和使用反义寡核苷酸已显示出盘状蛋白结构域受体1（DDR1）在肾纤维化中的重要性。但是，这些技术通过降低DDR1蛋白发挥作用，同时我们证明了用小分子抑制DDR1磷酸化的治疗潜力。迄今为止，在体内模型中产生选择性调节DDR1活性的选择性小分子的努力尚未成功。我们对DDR1和DDR2进行了并行的DNA编码文库筛选，发现了对DDR1的选择性比DDR2高的化学系列。以结构为导向的优化工作产生了有效的DDR1抑制剂2.45，它具有出色的激酶组选择性（在生化分析中比DDR2具有64倍的选择性），干净的体外安全性，以及良好的药代动力学和理化性质。根据需要，化合物2.45可以在体外调节DDR1的磷酸化，并防止胶原蛋白诱导的表达DDR1的肾上皮细胞活化。当采用治疗剂量方案时，化合物2.45保留Col4a3-/-小鼠（Alport综合征的临床前小鼠模型）的肾功能并减少组织损伤，表明在体内选择性抑制DDR1磷酸化的真正治疗价值。我们的结果可能具有更广泛的意义，因为Col4a3-/-小鼠也代表了慢性肾脏疾病的模型，该疾病影响了全球10％的人口。当采用治疗性给药方案时，45保留了Col4a3-/-小鼠（Alport综合征的临床前小鼠模型）中的肾功能并减少了组织损伤，表明在体内选择性抑制DDR1磷酸化的真正治疗价值。我们的结果可能具有更广泛的意义，因为Col4a3-/-小鼠也代表了慢性肾脏疾病的模型，该疾病影响了全球10％的人口。当采用治疗性给药方案时，45保留了Col4a3-/-小鼠（Alport综合征的临床前小鼠模型）中的肾功能并减少了组织损伤，表明在体内选择性抑制DDR1磷酸化的真正治疗价值。我们的结果可能具有更广泛的意义，因为Col4a3-/-小鼠也代表了慢性肾脏疾病的模型，该疾病影响了全球10％的人口。

更新日期：2018-11-19

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