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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	The effect of core replacement on S64315, a selective MCL-1 inhibitor, and its analogues Szabolcs Sipos , Balázs Bálint , Zoltán B. Szabó , Levente Ondi , Márton Csékei , Zoltán Szlávik , Ágnes Proszenyák , James B. Murray , James Davidson , Ijen Chen , Pawel Dokurno , Allan E. Surgenor , Christopher Pedder , Roderick E. Hubbard , Ana-Leticia Maragno , Maia Chanrion , Frederic Colland , Olivier Geneste , András Kotschy Acs Omega 6, 22073 - 22102 DOI: 10.1021/acsomega.1c02595 Diamond Proposal Number(s): [1857] Open Access Show Abstract ▼ Abstract: Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.	Aug 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-derived selective inhibitors of dual-specificity kinases DYRK1A and DYRK1B David Lee Walmsley , James B. Murray , Pawel Dokurno , Andrew J. Massey , Karen Benwell , Andrea Fiumana , Nicolas Foloppe , Stuart Ray , Julia Smith , Allan E. Surgenor , Thomas Edmonds , Didier Demarles , Mike Burbridge , Francisco Cruzalegui , Andras Kotschy , Roderick E. Hubbard Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00024 Open Access Show Abstract ▼ Abstract: The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.	Jun 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Design and synthesis of pyrrolo[2,3-d]pyrimidine-derived leucine-rich repeat kinase 2 (LRRK2) inhibitors using a checkpoint kinase 1 (CHK1)-derived crystallographic surrogate Douglas S. Williamson , Garrick P. Smith , Gitte K. Mikkelsen , Thomas Jensen , Pamela Acheson-Dossang , Lassina Badolo , Simon T. Bedford , Victoria Chell , I-Jen Chen , Pawel Dokurno , Morten Hentzer , Stephanie Newland , Stuart C. Ray , Terry Shaw , Allan E. Surgenor , Lindsey Terry , Yikang Wang , Kenneth V. Christensen Journal Of Medicinal Chemistry 56 DOI: 10.1021/acs.jmedchem.1c00720 Diamond Proposal Number(s): [27063, 2103, 5791, 6001] Open Access Show Abstract ▼ Abstract: Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson’s disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18/CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32. Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45, which demonstrated a favorable in vitro PK profile, although they displayed species disconnects in the in vivo PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.	Jun 2021
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based discovery of novel non-hydroxamate LpxC inhibitors with antibacterial activity Yousuke Yamada , Hajime Takashima , David Lee Walmsley , Fumihito Ushiyama , Yohei Matsuda , Harumi Kanazawa , Toru Yamaguchi-Sasaki , Nozomi Tanaka-Yamamoto , Junya Yamagishi , Risa Kurimoto-Tsuruta , Yuya Ogata , Norikazu Ohtake , Hayley Angove , Lisa Baker , Richard Harris , Alba Macias , Alan Robertson , Allan Surgenor , Hayato Watanabe , Koichiro Nakano , Masashi Mima , Kunihiko Iwamoto , Atsushi Okada , Iichiro Takata , Kosuke Hitaka , Akihiro Tanaka , Kiyoko Fujita , Hiroyuki Sugiyama , Roderick E. Hubbard Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01215 Diamond Proposal Number(s): [12428] Show Abstract ▼ Abstract: UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.	Nov 2020
I02-Macromolecular Crystallography	Discovery of S64315, a potent and selective Mcl-1 inhibitor Zoltan Szlavik , Marton Csekei , Attila Paczal , Zoltan B. Szabo , Szabolcs Sipos , Gabor Radics , Agnes Proszenyak , Balazs Balint , James Murray , James Davidson , Ijen Chen , Pawel Dokurno , Allan E Surgenor , Zoe Marie Daniels , Roderick E. Hubbard , Gaëtane Le Toumelin-Braizat , Audrey Claperon , Gaëlle Lysiak-Auvity , Anne-Marie Girard , Alain Bruno , Maia Chanrion , Frédéric Colland , Ana-Leticia Maragno , Didier Demarles , Olivier Geneste , Andras Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01234 Diamond Proposal Number(s): [2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.	Nov 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures Lisa M. Baker , Anthony Aimon , James B. Murray , Allan E. Surgenor , Natalia Matassova , Stephen D. Roughley , Patrick M. Collins , Tobias Krojer , Frank Von Delft , Roderick E. Hubbard Communications Chemistry 3 DOI: 10.1038/s42004-020-00367-0 Open Access Show Abstract ▼ Abstract: Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.	Sep 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity Zoltan Szlávik , Levente Ondi , Márton Csékei , Attila Paczal , Zoltán B. Szabó , Gábor Radics , James Murray , James Davidson , Ijen Chen , Ben Davis , Roderick E. Hubbard , Christopher Pedder , Pawel Dokurno , Allan Surgenor , Julia Smith , Alan Robertson , Gaetane Letoumelin-Braizat , Nicolas Cauquil , Marion Zarka , Didier Demarles , Francoise Perron-Sierra , Audrey Claperon , Frederic Colland , Olivier Geneste , András Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00134 Diamond Proposal Number(s): [17182, 1194, 2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.	Jul 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Design of leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from checkpoint kinase 1 (CHK1) Douglas S. Williamson , Garrick P. Smith , Pamela Acheson-Dossang , Simon T. Bedford , Victoria Chell , I-Jen Chen , Justus C. A. Daechsel , Zoe Daniels , Laurent David , Pawel Dokurno , Morten Hentzer , Martin C. Herzig , Roderick E. Hubbard , Jonathan D. Moore , James B. Murray , Samantha Newland , Stuart C. Ray , Terry Shaw , Allan E. Surgenor , Lindsey Terry , Kenneth Thirstrup , Yikang Wang , Kenneth V. Christensen Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b01186 Diamond Proposal Number(s): [5791, 12428, 2103, 14641, 5067] Show Abstract ▼ Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson’s disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]-pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-pt. mut. structure). Compound 22 was shown to be potent, moderately selective, orally available and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidney being 1.3 nM and 5 nM, respectively.	Oct 2017

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