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3. Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C

Author

Weiss, Andreas, primary, Lorthiois, Edwige, primary, Barys, Louise, primary, Beyer, Kim S., primary, Bomio-Confaglia, Claudio, primary, Burks, Heather, primary, Chen, Xueying, primary, Cui, Xiaoming, primary, de Kanter, Ruben, primary, Dharmarajan, Lekshmi, primary, Fedele, Carmine, primary, Gerspacher, Marc, primary, Guthy, Daniel Alexander, primary, Head, Victoria, primary, Jaeger, Ashley, primary, Núñez, Eloísa Jiménez, primary, Kearns, Jeffrey D., primary, Leblanc, Catherine, primary, Maira, Sauveur-Michel, primary, Murphy, Jason, primary, Oakman, Helen, primary, Ostermann, Nils, primary, Ottl, Johannes, primary, Rigollier, Pascal, primary, Roman, Danielle, primary, Schnell, Christian, primary, Sedrani, Richard, primary, Shimizu, Toshio, primary, Stringer, Rowan, primary, Vaupel, Andrea, primary, Voshol, Hans, primary, Wessels, Peter, primary, Widmer, Toni, primary, Wilcken, Rainer, primary, Xu, Kun, primary, Zecri, Frederic, primary, Farago, Anna F., primary, Cotesta, Simona, primary, and Brachmann, Saskia M., primary

Published
2023
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4. Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C

Author

Weiss, Andreas, primary, Lorthiois, Edwige, primary, Barys, Louise, primary, Beyer, Kim S., primary, Bomio-Confaglia, Claudio, primary, Burks, Heather, primary, Chen, Xueying, primary, Cui, Xiaoming, primary, de Kanter, Ruben, primary, Dharmarajan, Lekshmi, primary, Fedele, Carmine, primary, Gerspacher, Marc, primary, Guthy, Daniel Alexander, primary, Head, Victoria, primary, Jaeger, Ashley, primary, Núñez, Eloísa Jiménez, primary, Kearns, Jeffrey D., primary, Leblanc, Catherine, primary, Maira, Sauveur-Michel, primary, Murphy, Jason, primary, Oakman, Helen, primary, Ostermann, Nils, primary, Ottl, Johannes, primary, Rigollier, Pascal, primary, Roman, Danielle, primary, Schnell, Christian, primary, Sedrani, Richard, primary, Shimizu, Toshio, primary, Stringer, Rowan, primary, Vaupel, Andrea, primary, Voshol, Hans, primary, Wessels, Peter, primary, Widmer, Toni, primary, Wilcken, Rainer, primary, Xu, Kun, primary, Zecri, Frederic, primary, Farago, Anna F., primary, Cotesta, Simona, primary, and Brachmann, Saskia M., primary

Published
2023
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7. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors

Author

Lorthiois, Edwige, primary, Gerspacher, Marc, additional, Beyer, Kim S., additional, Vaupel, Andrea, additional, Leblanc, Catherine, additional, Stringer, Rowan, additional, Weiss, Andreas, additional, Wilcken, Rainer, additional, Guthy, Daniel A., additional, Lingel, Andreas, additional, Bomio-Confaglia, Claudio, additional, Machauer, Rainer, additional, Rigollier, Pascal, additional, Ottl, Johannes, additional, Arz, Dorothee, additional, Bernet, Pascal, additional, Desjonqueres, Gaëlle, additional, Dussauge, Solene, additional, Kazic-Legueux, Malika, additional, Lozac’h, Marie-Anne, additional, Mura, Christophe, additional, Sorge, Mickaël, additional, Todorov, Milen, additional, Warin, Nicolas, additional, Zink, Florence, additional, Voshol, Hans, additional, Zecri, Frederic J., additional, Sedrani, Richard C., additional, Ostermann, Nils, additional, Brachmann, Saskia M., additional, and Cotesta, Simona, additional

Published
2022
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8. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Author

Lovric, Svjetlana, Goncalves, Sara, Gee, Heon Yung, Oskouian, Babak, Srinivas, Honnappa, Choi, Won-Il, Shril, Shirlee, Ashraf, Shazia, Tan, Weizhen, Rao, Jia, Airik, Merlin, Schapiro, David, Braun, Daniela A., Sadowski, Carolin E., Widmeier, Eugen, Jobst-Schwan, Tilman, Schmidt, Johanna Magdalena, Girik, Vladimir, Capitani, Guido, Suh, Jung H., Lachaussée, Noëlle, Arrondel, Christelle, Patat, Julie, Gribouval, Olivier, Furlano, Monica, Boyer, Olivia, Schmitt, Alain, Vuiblet, Vincent, Hashmi, Seema, Wilcken, Rainer, Bernier, Francois P., Innes, A. Micheil, Parboosingh, Jillian S., Lamont, Ryan E., Midgley, Julian P., Wright, Nicola, Majewski, Jacek, Zenker, Martin, Schaefer, Franz, Kuss, Navina, Greil, Johann, Giese, Thomas, Schwarz, Klaus, Catheline, Vilain, Schanze, Denny, Franke, Ingolf, Sznajer, Yves, Truant, Anne S., Adams, Brigitte, Désir, Julie, Biemann, Ronald, Pei, York, Ars, Elisabet, Lloberas, Nuria, Madrid, Alvaro, Dharnidharka, Vikas R., Connolly, Anne M., Willing, Marcia C., Cooper, Megan A., Lifton, Richard P., Simons, Matias, Riezman, Howard, Antignac, Corinne, Saba, Julie D., and Hildebrandt, Friedhelm

Published
2017
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11. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C

Author

Weiss, Andreas, primary, Lorthiois, Edwige, additional, Barys, Louise, additional, Beyer, Kim S., additional, Bomio-Confaglia, Claudio, additional, Burks, Heather, additional, Chen, Xueying, additional, Cui, Xiaoming, additional, de Kanter, Ruben, additional, Dharmarajan, Lekshmi, additional, Fedele, Carmine, additional, Gerspacher, Marc, additional, Guthy, Daniel Alexander, additional, Head, Victoria, additional, Jaeger, Ashley, additional, Núñez, Eloísa Jiménez, additional, Kearns, Jeffrey D., additional, Leblanc, Catherine, additional, Maira, Sauveur-Michel, additional, Murphy, Jason, additional, Oakman, Helen, additional, Ostermann, Nils, additional, Ottl, Johannes, additional, Rigollier, Pascal, additional, Roman, Danielle, additional, Schnell, Christian, additional, Sedrani, Richard, additional, Shimizu, Toshio, additional, Stringer, Rowan, additional, Vaupel, Andrea, additional, Voshol, Hans, additional, Wessels, Peter, additional, Widmer, Toni, additional, Wilcken, Rainer, additional, Xu, Kun, additional, Zecri, Frederic, additional, Farago, Anna F., additional, Cotesta, Simona, additional, and Brachmann, Saskia M., additional

Published
2022
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12. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors.

Author

Lorthiois, Edwige, Gerspacher, Marc, Beyer, Kim S., Vaupel, Andrea, Leblanc, Catherine, Stringer, Rowan, Weiss, Andreas, Wilcken, Rainer, Guthy, Daniel A., Lingel, Andreas, Bomio-Confaglia, Claudio, Machauer, Rainer, Rigollier, Pascal, Ottl, Johannes, Arz, Dorothee, Bernet, Pascal, Desjonqueres, Gaëlle, Dussauge, Solene, Kazic-Legueux, Malika, and Lozac'h, Marie-Anne

Published
2022
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16. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12Cfor the Treatment of Solid Tumors

Author

Lorthiois, Edwige, Gerspacher, Marc, Beyer, Kim S., Vaupel, Andrea, Leblanc, Catherine, Stringer, Rowan, Weiss, Andreas, Wilcken, Rainer, Guthy, Daniel A., Lingel, Andreas, Bomio-Confaglia, Claudio, Machauer, Rainer, Rigollier, Pascal, Ottl, Johannes, Arz, Dorothee, Bernet, Pascal, Desjonqueres, Gaëlle, Dussauge, Solene, Kazic-Legueux, Malika, Lozac’h, Marie-Anne, Mura, Christophe, Sorge, Mickaël, Todorov, Milen, Warin, Nicolas, Zink, Florence, Voshol, Hans, Zecri, Frederic J., Sedrani, Richard C., Ostermann, Nils, Brachmann, Saskia M., and Cotesta, Simona

Abstract

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12Cinhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12Cinhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12CC12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Published
2022
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17. Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure

Author

Velcicky, Juraj, primary, Wilcken, Rainer, additional, Cotesta, Simona, additional, Janser, Philipp, additional, Schlapbach, Achim, additional, Wagner, Trixie, additional, Piechon, Philippe, additional, Villard, Frederic, additional, Bouhelal, Rochdi, additional, Piller, Fabian, additional, Harlfinger, Stephanie, additional, Stringer, Rowan, additional, Fehlmann, Dominique, additional, Kaupmann, Klemens, additional, Littlewood-Evans, Amanda, additional, Haffke, Matthias, additional, and Gommermann, Nina, additional

Published
2020
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26. Machine Learning Estimates of Natural Product Conformational Energies

Author

Rupp, Matthias, Bauer, Matthias R., Wilcken, Rainer, Lange, Andreas, Reutlinger, Michael, Boeckler, Frank M., and Schneider, Gisbert

Subjects
Magnetic Resonance Spectroscopy, Protein Conformation, Chemistry, Pharmaceutical, Normal Distribution, Molecular Dynamics Simulation, Molecular Dynamics, Computer Applications, Computational Chemistry, Artificial Intelligence, Chemical Biology, Myxococcales, Enzyme Inhibitors, lcsh:QH301-705.5, Computerized Simulations, Density Functional Theory, Adenosine Triphosphatases, Principal Component Analysis, Stochastic Processes, Molecular Structure, Computational Biology, Thiazoles, Chemistry, lcsh:Biology (General), Models, Chemical, Computer Science, Computer-Aided Design, Macrolides, ddc:004, Medicinal Chemistry, Algorithms, Software, Research Article
Abstract

Machine learning has been used for estimation of potential energy surfaces to speed up molecular dynamics simulations of small systems. We demonstrate that this approach is feasible for significantly larger, structurally complex molecules, taking the natural product Archazolid A, a potent inhibitor of vacuolar-type ATPase, from the myxobacterium Archangium gephyra as an example. Our model estimates energies of new conformations by exploiting information from previous calculations via Gaussian process regression. Predictive variance is used to assess whether a conformation is in the interpolation region, allowing a controlled trade-off between prediction accuracy and computational speed-up. For energies of relaxed conformations at the density functional level of theory (implicit solvent, DFT/BLYP-disp3/def2-TZVP), mean absolute errors of less than 1 kcal/mol were achieved. The study demonstrates that predictive machine learning models can be developed for structurally complex, pharmaceutically relevant compounds, potentially enabling considerable speed-ups in simulations of larger molecular structures., PLoS Computational Biology, 10 (1), ISSN:1553-734X, ISSN:1553-7358

Published
2014

38. Principles and Applicationsof Halogen Bonding inMedicinal Chemistry and Chemical Biology.

Author

Wilcken, Rainer, Zimmermann, Markus O., Lange, Andreas, Joerger, Andreas C., and Boeckler, Frank M.

Subjects
*HALOGENS, *PHARMACEUTICAL chemistry, *CHEMICAL biology, *MATERIALS science, *PROTEIN-ligand interactions, *DRUG development
Abstract

Halogen bonding has been known in material science fordecades,but until recently, halogen bonds in protein–ligand interactionswere largely the result of serendipitous discovery rather than rationaldesign. In this Perspective, we provide insights into the phenomenonof halogen bonding, with special focus on its role in drug discovery.We summarize the theoretical background defining its strength anddirectionality, provide a systematic analysis of its occurrence andinteraction geometries in protein–ligand complexes, and giverecent examples where halogen bonding has been successfully harnessedfor lead identification and optimization. In light of these data,we discuss the potential and limitations of exploiting halogen bondsfor molecular recognition and rational drug design. [ABSTRACT FROM AUTHOR]

Published
2013
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39. Dynamic conformational equilibria in the active states of KRAS and NRAS.

Author

Rennella E, Henry C, Dickson CJ, Georgescauld F, Wales TE, Erdmann D, Cotesta S, Maira M, Sedrani R, Brachmann SM, Ostermann N, Engen JR, Kay LE, Beyer KS, Wilcken R, and Jahnke W

Abstract

The design of potent RAS inhibitors benefits from a molecular understanding of the dynamics in KRAS and NRAS and their oncogenic mutants. Here we characterize switch-1 dynamics in GTP-state KRAS and NRAS by 31 P NMR, by 15 N relaxation dispersion NMR, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations. In GMPPNP-bound KRAS and NRAS, we see the co-existence of two conformational states, corresponding to an "inactive" state-1 and an "active" state-2, as previously reported. The KRAS oncogenic mutations G12D, G12C and G12V only slightly affect this equilibrium towards the "inactive" state-1, with rank order wt < G12C < G12D < G12V. In contrast, the NRAS Q61R oncogenic mutation shifts the equilibrium fully towards the "active" state-2. Our molecular dynamics simulations explain this by the observation of a transient hydrogen bond between the Arg61 side chain and the Thr35 backbone carbonyl oxygen. NMR relaxation dispersion experiments with GTP-bound KRAS Q61R confirm a drastic decrease in the population of state-1, but still detect a small residual population (1.8%) of this conformer. HDX-MS indicates that higher populations of state-1 correspond to increased hydrogen-deuterium exchange rates in some regions and increased flexibility, whereas low state-1 populations are associated with KRAS rigidification. We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Published
2024
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40. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS G12C for the Treatment of Solid Tumors.

Author

Lorthiois E, Gerspacher M, Beyer KS, Vaupel A, Leblanc C, Stringer R, Weiss A, Wilcken R, Guthy DA, Lingel A, Bomio-Confaglia C, Machauer R, Rigollier P, Ottl J, Arz D, Bernet P, Desjonqueres G, Dussauge S, Kazic-Legueux M, Lozac'h MA, Mura C, Sorge M, Todorov M, Warin N, Zink F, Voshol H, Zecri FJ, Sedrani RC, Ostermann N, Brachmann SM, and Cotesta S

Subjects
Animals, Humans, Mice, Disease Models, Animal, Drug Design, Mutation, Pyrazoles pharmacology, Pyrazoles therapeutic use, Neoplasms drug therapy, Neoplasms genetics, Proto-Oncogene Proteins p21(ras)
Abstract

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS G12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS G12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS G12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Published
2022
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41. Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties.

Author

Mohamed HA, Girgis NM, Wilcken R, Bauer MR, Tinsley HN, Gary BD, Piazza GA, Boeckler FM, and Abadi AH

Subjects
Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Carbolines chemistry, Carbolines pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Phosphodiesterase 5 Inhibitors chemistry, Phosphodiesterase 5 Inhibitors pharmacology, Recombinant Proteins antagonists & inhibitors, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Carbolines chemical synthesis, Models, Molecular, Phosphodiesterase 5 Inhibitors chemical synthesis
Abstract

New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC(50) values in the low nanomolar range were identified including compounds derived from l-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC(50) value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.

Published
2011
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