Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Ulrich Lücking; Lars Wortmann; Antje M Wengner; Julien Lefranc; Philip Lienau; Hans Briem; Gerhard Siemeister; Ulf Bömer; Karsten Denner; Martina Schäfer; Marcus Koppitz; Knut Eis; Florian Bartels; Benjamin Bader; Wilhelm Bone; Dieter Moosmayer; Simon J Holton; Uwe Eberspächer; Joanna Grudzinska-Goebel; Christoph Schatz; Gesa Deeg; Dominik Mumberg; Franz von Nussbaum

doi:10.1021/acs.jmedchem.0c00369

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

J Med Chem. 2020 Jul 9;63(13):7293-7325. doi: 10.1021/acs.jmedchem.0c00369. Epub 2020 Jun 28.

Authors

Ulrich Lücking¹, Lars Wortmann¹, Antje M Wengner¹, Julien Lefranc¹, Philip Lienau¹, Hans Briem¹, Gerhard Siemeister¹, Ulf Bömer¹, Karsten Denner¹, Martina Schäfer¹, Marcus Koppitz¹, Knut Eis¹, Florian Bartels¹, Benjamin Bader¹, Wilhelm Bone¹, Dieter Moosmayer¹, Simon J Holton¹, Uwe Eberspächer¹, Joanna Grudzinska-Goebel¹, Christoph Schatz¹, Gesa Deeg¹, Dominik Mumberg¹, Franz von Nussbaum¹

Affiliation

¹ Research & Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.

PMID: 32502336
DOI: 10.1021/acs.jmedchem.0c00369

Abstract

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics*
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
Ataxia Telangiectasia Mutated Proteins / chemistry
Ataxia Telangiectasia Mutated Proteins / metabolism
Biological Availability
Carboplatin / administration & dosage
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Cytochrome P-450 CYP2C8 Inhibitors / chemistry
Cytochrome P-450 CYP2C8 Inhibitors / pharmacology
DNA Repair / drug effects
Dogs
Drug Discovery
Drug Screening Assays, Antitumor
Drug Stability
Female
Humans
Mice, SCID
Microsomes, Liver / drug effects
Morpholines / administration & dosage*
Morpholines / chemistry
Morpholines / pharmacokinetics*
Pyrazoles / administration & dosage*
Pyrazoles / chemistry
Pyrazoles / pharmacokinetics*
Rats, Wistar
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
BAY 1895344
Cytochrome P-450 CYP2C8 Inhibitors
Morpholines
Pyrazoles
Carboplatin
ATM protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins

Associated data

ClinicalTrials.gov/NCT03188965