Jonathan B. Houze

Abstract The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. Significance: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. See related commentary by Leber et al., p. 1511. This article is highlighted in the In This Issue feature, p. 1494

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTThe Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of TaxolPaul A. Wender, Neil F. Badham, Simon P. Conway, Paul E. Floreancig, Timothy E. Glass, Jonathan B. Houze, Nancy E. Krauss, Daesung Lee, Daniel G. Marquess, Paul L. McGrane, Wei Meng, Michael G. Natchus, Anthony J. Shuker, James C. Sutton, and Richard E. TaylorView Author Information Department of Chemistry, Stanford University Stanford, California 94305 Cite this: J. Am. Chem. Soc. 1997, 119, 11, 2757–2758Publication Date (Web):March 19, 1997Publication History Received9 October 1996Published online19 March 1997Published inissue 1 March 1997https://pubs.acs.org/doi/10.1021/ja963539zhttps://doi.org/10.1021/ja963539zrapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views7008Altmetric-Citations213LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Cyclization,Hydroxyls,Inorganic carbon compounds,Precursors,Pyridines Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTThe Pinene Path to Taxanes. 5. Stereocontrolled Synthesis of a Versatile Taxane PrecursorPaul A. Wender, Neil F. Badham, Simon P. Conway, Paul E. Floreancig, Timothy E. Glass, Christian Gränicher, Jonathan B. Houze, Jan Jänichen, Daesung Lee, Daniel G. Marquess, Paul L. McGrane, Wei Meng, Thomas P. Mucciaro, Michel Mühlebach, Michael G. Natchus, Holger Paulsen, David B. Rawlins, Jeffrey Satkofsky, Anthony J. Shuker, James C. Sutton, Richard E. Taylor, and Katsuhiko TomookaView Author Information Department of Chemistry, Stanford University Stanford, California 94305 Cite this: J. Am. Chem. Soc. 1997, 119, 11, 2755–2756Publication Date (Web):March 19, 1997Publication History Received9 October 1996Published online19 March 1997Published inissue 1 March 1997https://pubs.acs.org/doi/10.1021/ja9635387https://doi.org/10.1021/ja9635387rapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views7328Altmetric-Citations150LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Alcohols,Carbonyls,Ketones,Precursors,Redox reactions Get e-Alerts

Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39)NH(2).