Andreas Goutopoulos

Integrating Fragment Screening and Covalent Chemistry to Drug DNA-Binding Proteins: RAD52 as a Case Study

Nicolas Bocquet, Alessandro Potenza, Jason Clochard, Anika Kuster et autres

Protein-DNA interfaces are central to genome maintenance but remain challenging targets for small-molecule discovery because they are often broad, polar, solvent exposed, and lack classical druggable pockets. Here, we establish a structure-guided strategy to chemically target such interfaces by combining fragment-based identification …

ch, cn, gb, il (code pays fourni par la source)

Integrating Fragment Screening and Covalent Chemistry to Drug DNA-Binding Proteins: RAD52 as a Case Study

Nicolas Bocquet, Alessandro Potenza, Jason Clochard, Anika Kuster et autres

Protein-DNA interfaces are central to genome maintenance but remain challenging targets for small-molecule discovery because they are often broad, polar, solvent exposed, and lack classical druggable pockets. Here, we establish a structure-guided strategy to chemically target such interfaces by combining fragment-based identification …

ch, cn, gb, il (code pays fourni par la source)

Abstract B022: FORX-428: A best-in class PARG inhibitor with promising anti-tumor activity in preclinical cancer models

Frank T. Zenke, Ulrich Lücking, Olivier Querolle, Andreas Goutopoulos et autres

Abstract The formation of poly (ADP-ribose) (PAR) chains from NAD+ catalyzed by PARP enzymes is a pivotal posttranslational modification at sites of DNA lesions or stalled replication forks and serves as a scaffold to recruit DNA repair proteins. Equally important as the …

ch (code pays fourni par la source)

Abstract 3366: FoRx-06-428 is a novel PARG inhibitor with potent anti-tumor efficacy in preclinical cancer models

Olivier Querolle, Ulrich Lücking, Luca Iacovino, Alena Freudenmann et autres

Abstract The formation of poly(ADP-ribose) (PAR) chains from NAD+ precursors by PARP enzymes is a characteristic posttranslational modification during DNA damage repair. PAR chains function as docking platforms for DNA repair proteins that are required to resolve DNA lesions. Equally important is …

ch (code pays fourni par la source)

Abstract 1397: A phenotypic-based drug discovery approach against tumors with MTAP loss

Andreas Goutopoulos, Iris Amanati, Avital Hay-Koren, Ali R. Fattaey et autres

Abstract The Methylthioadenosine phosphorylase (MTAP) gene is in chromosome 9q21 location, which includes p16/CDKNA and is homozygously deleted in about 15% of all cancers, including a large proportion of gliomas, mesotheliomas and T cell lymphomas. MTAP cleaves methylthioadenosine (MTA), a byproduct of …

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Abstract 2326: Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor

Andreas Goutopoulos, Iris Amanati, Ali R. Fattaey, Avital Hay-Koren et autres

Abstract ACSS2 is a nucleo-cytoplasmic enzyme that converts acetate into Acetyl-CoA. In many tumor types ACSS2 is dramatically upregulated in response to the hypoxic and lipid-depleted conditions often encountered in the tumor microenvironment. In these conditions, ACSS2 allows tumor cells to switch …

fr (code pays fourni par la source)

Phase 1 first-in-human trial of MTB-9655, the first oral inhibitor of ACSS2, in patients with advanced solid tumors.

Ruth Perets, Ravit Geva, Meredith Ann McKean, Andreas Goutopoulos et autres

e20609 Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified …

il, us (code pays fourni par la source)

A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in subjects with advanced solid tumors.

Mark M. Yarchoan, John D. Powderly, Bruno R. Bastos, Thomas Benjamin Karasic et autres

3005 Background: TPST-1120 is a first-in-class oral therapy that inhibits PPARα, a transcription factor that regulates fatty acid oxidation (FAO). TPST-1120 has diverse mechanisms of anti-tumor activity in preclinical studies, including inhibiting tumor proliferation, increasing the anti-angiogenic factor thrombospondin 1, and reducing …

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Corrigendum to “Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors” [Bioorgan. Med. Chem. Lett. 50 (2021) 128352]

Yufang Xiao, Bayard R. Huck, Ruoxi Lan, Lizbeth DeSelm et autres

us, de, it (code pays fourni par la source)

Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered Cancers

Lizbeth DeSelm, Bayard R. Huck, Ruoxi Lan, Constantin Neagu et autres

Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood …

us, de (code pays fourni par la source)

Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity

Hui Qiu, Zahid Ali, Julian Bowlan, Richard D. Caldwell et autres

Abstract Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory …

us, de, it, ch (code pays fourni par la source)

Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors

Yufang Xiao, Bayard R. Huck, Ruoxi Lan, Lizbeth DeSelm et autres

de, it, us (code pays fourni par la source)