Maria Ahn

Abstract 4756: Evaluation of strategies to target the Myc oncogene

Maria Ahn, Aimee Blair, Juan A. Bueren‐Calabuig, Barbara Farkas et autres

Abstract Aim: Myc overexpression or dysregulation is a hallmark of most malignancies, yet targeting of Myc-driven cancers remains a clinically unmet need1. Both indirect and direct modalities of Myc inhibition have been evaluated. Indirect Myc targeting via inhibition of its binding to …

Abstract 3053: Combination of the MDM2 antagonist ASTX295 and Olaparib as a novel treatment option for BRCA2 mutant, TP53 wild-type solid tumors

Antonio Morales, Joanna Obacz, Bryn S. Hardwick, Adam Jackson et autres

Abstract p53, encoded by the TP53 tumor suppressor gene, is a critical regulator of the cellular response to stress such as DNA damage and oncogenic signaling. p53 triggers the transcriptional program that dictates cell-fate decisions, including cell cycle checkpoint activation, senescence, and …

Abstract B097: Structural Interpretations of High-throughput PI3K Pathway CRISPR Base-editing Data

Benoît Baillif, Katrina McCarten, Barbara Abreu, Lisa Koob et autres

Abstract Detailed knowledge of protein function and structure can facilitate drug discovery. Although protein active sites are the most common point of intervention by small molecule therapeutics, many targets lack a precedented, druggable site that can be selectively targeted. In these cases, …

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Abstract 1627: Switching cell fate from senescence to apoptosis by the combination of a p53 corrector with the MDM2 antagonist ASTX295

George A. Ward, Judit Espana-Agusti, Keisha Hearn, Mark L. Wade et autres

Abstract Background: ASTX295 is a potent MDM2 antagonist designed to have a shorter half-life (t1/2 4-6 hours in plasma), which leads to an improved safety profile (bone-marrow sparing), making it more amenable to combinations compared to other MDM2 antagonists. The recent success …

Abstract 5331: Orthosteric CDK2 kinase inhibitors have a distinctive profile when compared to genetic perturbation of CDK2 in CCNE1-amplified and non-amplified tumor cell lines

Joanne M. Munck, Susan J. Tudhope, Kleopatra Papa, Suzanne Kyle et autres

Abstract Aim: There has been renewed interest in pursuing cyclin-dependent kinase 2 (CDK2) as a therapeutic target for cancer treatment, given its essential role in driving the survival of CCNE1-amplified tumors and mediating resistance to CDK4/6 inhibitor treatment in estrogen receptor positive …

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ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies

Sandrine Jayne, Harriet S. Walter, Andrea Biondo, Martin Sims et autres

Introduction: Targeting the Mouse double minute 2 (MDM2)-p53 interaction, results in reactivation of wild-type (WT) TP53 and induction of transcriptional targets, causing cell death and cell cycle arrest. However, previous clinical studies with MDM2 inhibitors have shown limited efficacy and on-target thrombocytopenia. …

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Abstract 6588: Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile

Maria Ahn, Luke Bevan, Ildiko M. Buck, Céline Cano et autres

Abstract In response to cellular stress, the tumor suppressor p53 is activated to modulate cell cycle progression, DNA repair, and apoptosis. Inhibition of the MDM2-p53 interaction in tumors carrying wild-type p53 prevents its degradation and can reactivate p53 to elicit an anti-cancer …

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Abstract 3333: Targeting the MDM2-p53 interaction: Time- and concentration-dependent studies in tumor and normal human bone marrow cells reveal strategies for an enhanced therapeutic index

Elaine Willmore, Maria Ahn, Suzanne Kyle, Yan Zhao et autres

Abstract Aim We aimed to design an MDM2-p53 antagonist with a differentiated tolerability profile that could be used to treat patients with wild-type TP53 malignancies. As part of an alliance between Newcastle University, Astex Pharmaceuticals, and Cancer Research Horizons, we discovered ASTX295, …

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Abstract 666: ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants

Dean Anthony Fennell, Joanna Działo, Jan Rogel, Daniel Faulkner et autres

Abstract Mesothelioma is a universally lethal, rare cancer caused by asbestos that is lacking effective targeted treatments, particularly in the relapsed setting. P53 is predominantly wildtype (WT 83%) but is likely restrained by MDM2 particularly in the context of 9p21 deletion, a …

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Abstract 667: Identification of biomarkers of response to MDM2 inhibition in solid tumours using computational, multi-omics approaches

Harpreet Kaur Saini, Maria Ahn, George Ward, Justyna Kucia-Tran et autres

Abstract Background High-throughput drug screening and computational methods to associate genomic features of cell lines to drug sensitivity are valuable tools for predicting biomarkers of sensitivity. In addition, integrating genomic features to expression-based patterns could improve biomarker prediction and patient stratification. Particularly …

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Abstract A110: Identifying sensitive patient populations for CDK7 inhibitors using cell panel screens and bioinformatic approaches

Keisha Hearn, Maria Ahn, Luke Bevan, Jessica L. Brothwood et autres

Abstract Background Dysregulation of cell cycle and transcriptional processes promote tumorigenesis and tumor growth. Due to its dual role in regulating both cellular processes, CDK7 is an attractive therapeutic target, with several CDK7 inhibitors in clinical trials. Preclinical data suggests that such …

Abstract 1652: Development of a potent class of small molecule inhibitors of the MDM2-p53 protein-protein interaction

Lynsey Fazal, Maria Ahn, Luke Bevan, Ildiko M. Buck et autres

Abstract In response to cellular stress, the p53 tumor suppressor is activated to modulate cell cycle progression, DNA repair, and cell death. The activity of p53 is tightly regulated by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. Inhibition …