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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
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
I04-Macromolecular Crystallography	Discovery of AZD4747, a potent and selective inhibitor of mutant GTPase KRASG12C with demonstrable CNS penetration Jason G. Kettle , Sharan K. Bagal , Derek Barratt , Michael S. Bodnarchuk , Scott Boyd , Erin Braybrooke , Jason Breed , Doyle J. Cassar , Sabina Cosulich , Michael Davies , Nichola L. Davies , Chao Deng , Andrew Eatherton , Laura Evans , Lyman J. Feron , Shaun Fillery , Emma Gleave , Frederick W. Goldberg , Miguel A. Cortés González , Carine Guerot , Afreen Haider , Stephanie Harlfinger , Rachel Howells , Anne Jackson , Peter Johnström , Paul D. Kemmitt , Alex Koers , Mikhail Kondrashov , Gillian M. Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Megan Mylrea , Samuel Nash , Michael J. Niedbala , Alison Peter , Christopher Phillips , Kurt Pike , Piotr Raubo , Graeme R. Robb , Sarah Ross , Matthew G. Sanders , Magnus Schou , Iain Simpson , Oliver Steward Journal Of Medicinal Chemistry 66, 9147 - 9160 DOI: 10.1021/acs.jmedchem.3c00746 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	Jul 2023
I03-Macromolecular Crystallography	Optimization of hERG and pharmacokinetic properties for basic dihydro-8H-purin-8-one inhibitors of DNA-PK Frederick W. Goldberg , Attilla K. T. Ting , David Beattie , Gillian M. Lamont , Charlene Fallan , M. Raymond V. Finlay , Beth Williamson , Marianne Schimpl , Alexander R. Harmer , Oladipupo B. Adeyemi , Pär Nordell , Anna S. Cronin , Mercedes Vazquez-Chantada , Derek Barratt , Antonio Ramos-Montoya , Elaine B. Cadogan , Barry R. Davies Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.2c00172 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10–15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pKa, to identify compound 18, which combines low hERG activity (IC50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.	Jul 2022
I04-Macromolecular Crystallography	Discovery of AZD4625, a covalent allosteric inhibitor of the mutant GTPase KRASG12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Scott Boyd , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Nichola L. Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma S. Gleave , Frederick W. Goldberg , Lyndsey Hanson , Stephanie Harlfinger , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Gillian Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Michael J. Niedbala , Christopher Phillips , Radek Polanski , Piotr Raubo , Graeme Robb , David M. Robinson , Sarah Ross , Matthew G. Sanders , Michael Tonge , Rebecca Whiteley , Stephen Wilkinson , Junsheng Yang , Wenman Zhang Journal Of Medicinal Chemistry 65, 6940 - 6952 DOI: 10.1021/acs.jmedchem.2c00369 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	May 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRAS G12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma Gleave , Frederick W. Goldberg , Stephanie Harlfinger , Lyndsey Hanson , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Jennifer K. Kingston , Scott Lamont , Hilary J. Lewis , Songlei Li , Libin Liu , Derek Ogg , Christopher Phillips , Radek Polanski , Graeme Robb , David Robinson , Sarah Ross , James M. Smith , Michael Tonge , Rebecca Whiteley , Junsheng Yang , Longfei Zhang , Xiliang Zhao Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01720 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.	Feb 2020
I03-Macromolecular Crystallography	The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor Frederick Woolf Goldberg , M. Raymond V. Finlay , Attilla Ting , David Beattie , Gillian Lamont , Charlene Fallan , Gail Wrigley , Marianne Schimpl , Martin R. Howard , Beth Williamson , Mercedes Vazquez-Chantada , Derek Barratt , Barry Davies , Elaine Cadogan , Antonio Ramos Montoya , Emma Dean Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01684 Open Access Show Abstract ▼ Abstract: DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity whilst improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-targets in the protein kinome, and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).	Dec 2019
I04-Macromolecular Crystallography	Optimization of highly kinase selective Bis-anilino pyrimidine PAK1 inhibitors William Mccoull , Edward J. Hennessy , Kevin Blades , Claudio Chuaqui , James E. Dowling , Andrew D. Ferguson , Frederick W. Goldberg , Nicholas Howe , Christopher R. Jones , Paul D. Kemmitt , Gillian Lamont , Jeffrey G. Varnes , Richard A. Ward , Bin Yang Acs Medicinal Chemistry Letters 7, 1118 - 1123 DOI: 10.1021/acsmedchemlett.6b00322 Show Abstract ▼ Abstract: Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.	Dec 2016
I04-Macromolecular Crystallography	Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity William Mccoull , Edward J. Hennessy , Kevin Blades , Matthew R. Box , Claudio Chuaqui , James E. Dowling , Christopher D. Davies , Andrew D. Ferguson , Frederick W. Goldberg , Nicholas J. Howe , Paul D. Kemmitt , Gillian M. Lamont , Katrina Madden , Claire Mcwhirter , Jeffrey G. Varnes , Richard A. Ward , Jason D. Williams , Bin Yang Medchemcomm 5, 1533 - 1539 DOI: 10.1039/C4MD00280F Show Abstract ▼ Abstract: A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular potency and has utility as a tool compound for target validation studies.	Aug 2014

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