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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	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 Y. S. Balazs , Bernard Barlaam , Michael S. Bodnarchuk , Gavin W. Collie , Ian L. Dale , Christopher R. Denz , Lisa Drew , Scott D. Edmondson , Jun Fan , Stephen Fawell , Frederick W. Goldberg , Ariamala Gopalsamy , Michael Grondine , Grace Guo , Sudhir M. Hande , Holia Hatoum-Mokdad , Alexander W. Hird , Rachel Howells , Jessie Hao-Ru Hsu , Jessica Hudson , Anne Jackson , Michelle L. Lamb , Gillian M. Lamont , Scott Lamont , Phillip A. Lichtor , Lisa Mcwilliams , David Milne , Scott N. Mlynarski , Priyanka Narasimhan , Matthew F. Peters , Alexander Pflug , Hannah Kate Pollard , Meile Qin , Corinne Reimer , Kevin J. Robbins , James Robinson , Li Sha , Hongyao She , James E. Sheppeck , Baljinder Singh , Kun Song , Qibin Su , Reem Telmesani , Scott Throner , Christina Vasalou , Lei Wang , Yanjun Wang , David M. Wilson , Poppy Winlow , Wenzhan Yang , Tieguang Yao , Yun Zhang , Zirong Zhang , Diana Zindel , Jeffrey W. Johannes Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c01478 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: 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 in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity. To this end, we report the discovery of AZD8421, a potent and highly selective CDK2 inhibitor, which exhibits superior selectivity for CDK2 over CDK1, other CDK family members, and the broader human kinome. AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent.	Sep 2025
I04-Macromolecular Crystallography	Discovery and optimization of pyrazine carboxamide AZ3246, a selective HPK1 inhibitor Jason D. Shields , David Baker , Amber Y. S. Balazs , Gayathri Bommakanti , Robert Casella , Shenggen Cao , Steve Cook , Randolph A. Escobar , Stephen Fawell , Francis D. Gibbons , Kathryn A. Giblin , Frederick W. Goldberg , Eric Gosselin , Tyler Grebe , Niresh Hariparsad , Holia Hatoum-Mokdad , Rachel Howells , Samantha J. Hughes , Anne Jackson , Iswarya Karapa Reddy , Jason G. Kettle , Gillian M. Lamont , Scott Lamont , Min Li , Sten O. Nilsson Lill , Deanna A. Mele , Anthony J. Metrano , Adelphe M. Mfuh , Lucas A. Morrill , Bo Peng , Alexander Pflug , Theresa A. Proia , Hadi Rezaei , Ryan Richards , Magdalena Richter , Kevin J. Robbins , Maryann San Martin , Marianne Schimpl , Alwin G. Schuller , Li Sha , Minhui Shen , James E. Sheppeck , Meha Singh , Stephen Stokes , Kun Song , Yuanyuan Sun , Haoran Tang , David J. Wagner , Jianyan Wang , Yanjun Wang , David M. Wilson , Allan Wu , Chengyan Wu , Dedong Wu , Ye Wu , Kevin Xu , Yue Yang , Tieguang Yao , Minwei Ye , Andrew X. Zhang , Hui Zhang , Xiang Zhai , Yanxiao Zhou , Robert E. Ziegler , Neil P. Grimster Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02631 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: 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 enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.	Feb 2025
I03-Macromolecular Crystallography	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 Y. S. Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin J. Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie J. B. Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Lisa Mcwilliams , Mark J. O’connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andy Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01725 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: 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 optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.	Dec 2024
I04-Macromolecular Crystallography	Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors Neil P. Grimster , Lakshmaiah Gingipalli , Amber Balazs , Bernard Barlaam , Scott Boiko , Scott Boyd , Hannah Dry , Frederick W. Goldberg , Tim Ikeda , Tony Johnson , Sameer Kawatkar , Paul Kemmitt , Scott Lamont , Olivier Lorthioir , Adelphe Mfuh , Joe Patel , Andy Pike , Jon Read , Romulo Romero , Ujjal Sarkar , Li Sha , Iain Simpson , Kun Song , Qibin Su , Haixia Wang , David Watson , Allan Wu , Troy E. Zehnder , Xiaolan Zheng , Shaolu Li , Zhiqiang Dong , Dejian Yang , Yanwei Song , Peng Wang , Xuemei Liu , James E. Dowling , Scott D. Edmondson Bioorganic & Medicinal Chemistry Letters 91 DOI: 10.1016/j.bmcl.2023.129352 Show Abstract ▼ Abstract: Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.	Jul 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	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 Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Scott Martin , Lisa Mcwilliams , Mark J. O'Connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andrew Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01012 Diamond Proposal Number(s): [14631, 17180, 20015] Show Abstract ▼ Abstract: 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 PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.	Sep 2021
I03-Macromolecular Crystallography	Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist James S. Scott , Thomas A. Moss , Amber Balazs , Bernard Barlaam , Jason Breed , Rodrigo J. Carbajo , Elisabetta Chiarparin , Paul R. J. Davey , Oona Delpuech , Stephen Fawell , David I. Fisher , Sladjana Gagrica , Eric T. Gangl , Tyler Grebe , Ryan D. Greenwood , Sudhir Hande , Holia Hatoum-Mokdad , Kara Herlihy , Samantha Hughes , Thomas A. Hunt , Hoan Huynh , Sophie L. M. Janbon , Tony Johnson , Stefan Kavanagh , Teresa Klinowska , Mandy Lawson , Andrew S. Lister , Stacey Marden , Dermot F. Mcginnity , Christopher J. Morrow , J. Willem M. Nissink , Daniel H. O’donovan , Bo Peng , Radoslaw Polanski , Darren S. Stead , Stephen Stokes , Kumar Thakur , Scott R. Throner , Michael J. Tucker , Jeffrey Varnes , Haixia Wang , David M. Wilson , Dedong Wu , Ye Wu , Bin Yang , Wenzhan Yang Journal Of Medicinal Chemistry 63, 14530 - 14559 DOI: 10.1021/acs.jmedchem.0c01163 Show Abstract ▼ Abstract: Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.	Sep 2020

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