Heightman et al., “Structure–Activity and Structure–Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein–Protein Interaction.” J. Med. Chem., 2019

/in , ,

Heightman et al., “Structure–Activity and Structure–Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein–Protein Interaction.” J. Med. Chem., 2019

DOI: 10.1021/acs.jmedchem.9b00279

Deaton et al., “The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.” Bioorganic & Medicinal Chemistry, 2019

/in , ,

Deaton et al., “The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.” Bioorganic & Medicinal Chemistry, 2019

doi.org/10.1016/j.bmc.2019.02.017

O’Reilly et al., “Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design.” Drug Discovery Today, 2019

/in , ,

O’Reilly et al., “Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design.” Drug Discovery Today, 2019

doi.org/10.1016/j.drudis.2019.03.009

Ceska et al., “Cryo-EM in drug discovery” Biochemical Society Transactions (2019)

/in , ,

Ceska et al., “Cryo-EM in drug discovery” Biochemical Society Transactions (2019)

10.1042/BST20180267

Grainger et al., “Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroarylation of Cyclic Amines.” Chemical Science 2019

/in , ,

Grainger et al., “Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroarylation of Cyclic Amines.” Chemical Science 2019

10.1039/C8SC04789H

Šuštić et al., “A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers”; Genome Med. 2018

/in , ,

Šuštić et al., “A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers”; Genome Med. 2018

https://doi.org/10.1186/s13073-018-0600-z

Lebraud., et al., “Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe.” Chem. Sci. October 2018, Issue 37

/in , ,

Lebraud., et al., “Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe.” Chem. Sci. October 2018, Issue 37

Doi.org/10.1039/c8sc02754d

Perera TPS, et al., “Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor.” Mol Cancer Ther, 2017, Vol 16, No. 6 pp. 1010– 1020

/in , ,

Perera TPS, et al., “Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor.” Mol Cancer Ther, 2017, Vol 16, No. 6 pp. 1010– 1020.

DOI: 10.1158/1535-7163.MCT-16-0589

Jubb et al., “COSMIC-3D provides structural perspectives on cancer genetics for drug discovery.” Nature Genetics 2018

/in , ,

Jubb, HC et al., “COSMIC-3D provides structural perspectives on cancer genetics for drug discovery.” Nature Genetics. 2018

DOI: 10.1038/s41588-018-0214-9

Johnson et al., “A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660).” J. Med. Chem., 2018

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Abstract
Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP–XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).

View further details below:
Johnson et al., “A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660).” J. Med. Chem., 2018

DOI: 10.1021/acs.jmedchem.8b00900