Zhijun Kang

Discovery of 6-[(3 S ,4 S )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor

Barbara Czakó, Yuting Sun, Timothy J. McAfoos, Jason B. Cross et autres

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its …

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Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer

Vrutant V. Shah, Aundrietta D. Duncan, Shiming Jiang, Sabrina A. Stratton et autres

Abstract Conditional overexpression of histone readerTripartitemotif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast …

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Author Correction: An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Victoria C. Yan et autres

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An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Victoria C. Yan et autres

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Discovery of IPN60090, a Clinical Stage Selective Glutaminase‑1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

Michael Soth, Kang Le, Maria Emilia Di Francesco, Matthew M. Hamilton et autres

Abstract Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing …

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Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Abstract Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical …

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An Enolase Inhibitor for the Targeted Treatment of ENO1-Deleted Cancers

Yu-Hsi Lin, Nikunj Satani, Victoria C. Yan, Jeffrey J. Ackroyd et autres

Metabolomic and figure source data discussed in the manuscript "An Enolase Inhibitor for the Targeted Treatment of ENO1-Deleted Cancers" are included

Abstract C036: Discovery of IACS-13909, an allosteric SHP2 inhibitor that overcomes multiple mechanisms underlying osimertinib resistance

Yuting Sun, Brooke A. Meyers, Sarah B. Johnson, Angela L. Harris et autres

Abstract Osimertinib, a third generation EGFR inhibitor, is a front-line therapy for EGFR mutated non-small lung cancer (NSCLC). The long-term effectiveness of osimertinib is limited by acquired resistance. Clinically identified resistance mechanisms include EGFR-dependent mechanisms such as mutations on EGFR that preclude …

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Abstract 1655: Discovery and development of IACS-010759, a novel inhibitor of Complex I currently in phase I studies to exploit oxidative phosphorylation dependency in acute myeloid leukemia and solid tumors

Maria Emilia Di Francesco, Joseph R. Marszalek, Timothy J. McAfoos, Christopher L. Carroll et autres

Abstract Over the past few years we and others reported that specific populations of tumor cells including AML, subsets of lymphoma, glioblastoma, triple negative breast cancer (TNBC), melanoma and pancreatic ductal adenocarcinoma (PDAC) are highly dependent upon oxidative phosphorylation (OXPHOS) to meet …

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An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Jennifer R. Molina, Yuting Sun, Marina N. Protopopova, Sonal Gera et autres

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Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate

Christopher J. Helal, Eric P. Arnold, Tracey L. Boyden, Cheng Chang et autres

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 ( 30 ) was subsequently identified as a preclinical candidate …

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Abstract 4971: IACS-010759, a novel inhibitor of complex I in Phase I clinical development to target OXPHOS dependent tumors

Jennifer R. Molina, Madhavi L. Bandi, Jennifer Bardenhagen, Christopher Aaron Bristow et autres

Abstract Tumor cells depend on both glycolysis and oxidative phosphorylation (OXPHOS) for energy and biomass production to support cell proliferation. Recent data has demonstrated a dependence of various tumor types on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive …

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