Amber Balazs

Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome

Avipsa Ghosh, Afshan Ahmed, Konstantina Amoiradaki, Amber Balazs et autres

Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors …

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Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor

Jason D. Shields, David J Baker, Amber Balazs, Gayathri Bommakanti et autres

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of …

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Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor

Jeffrey W. Johannes, Amber Balazs, Derek G. Barratt, Michał Biśta et autres

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly …

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Structural and Physicochemical Features of Oral PROTACs

Markus Schade, James S. Scott, Thomas G. Hayhow, Andy Pike et autres

pharmacokinetic properties in mouse, rat, and dog of four clinical oral PROTACs and compare with an internally derived data set. We use NMR to determine 3D molecular conformations and structural preorganization free in solution, and we introduce the new experimental descriptors, solvent-exposed …

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Discovery, preclinical validation and early human imaging with [11C]AZ14193391 – the first blood-brain barrier permeable and subtype selective PARP1 PET radioligand

Miguel Angel Cortes Gonzalez, Aurelija Jučaitė, Zsolt Cselényi, Peter Johnström et autres

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors

Neil P. Grimster, Lakshmaiah Gingipalli, Amber Balazs, Bernard C. Barlaam et autres

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Optimization of a Series of Novel, Potent and Selective Macrocyclic SYK Inhibitors

Neil Patrick Grimster, Lakshmaiah Gingipalli, Amber Balazs, Bernard C. Barlaam et autres

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Abstract 5076: Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography

Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce et autres

Abstract The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors …

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Abstract 6302: Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper

Avipsa Ghosh, Sudhir Mahadeo Hande, Amber Balazs, Derek G. Barratt et autres

Abstract PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and PARP1 trapping onto the DNA. All known clinical PARP1 inhibitors bind at the same site at the catalytic center of the enzyme. However, …

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Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs

Jeffrey W. Johannes, Amber Balazs, Derek G. Barratt, Michał Biśta et autres

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over …

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Abstract 296: Structure-based and property-based drug design of AZD5305, a highly selective PARP1 inhibitor and trapper

Sudhir Mahadeo Hande, Amber Balazs, Sébastien L. Degorce, Kevin J. Embrey et autres

Abstract Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and have seen widespread success. However, as a class, these drugs are not without adverse events which have limited their ability to …

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Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics

Amber Balazs, Nichola L. Davies, David Longmire, Martin John Packer et autres

Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion …

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