A Phase 1, first-in-human study of EP31670, a dual BET and CBP/p300 inhibitor in patients with targeted advanced solid tumors and Hematological Malignancies

Start Date21 Dec 2022

Sponsor / Collaborator

Epigenetix

100 Clinical Results associated with NEO-2734

100 Translational Medicine associated with NEO-2734

100 Patents (Medical) associated with NEO-2734

Literatures (Medical) associated with NEO-2734

01 Jun 2024·The Journal of Pathology

Co‐targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor‐null prostate cancer

Article

Author: Hedwards, Shelley ; Keerthikumar, Shivakumar ; Choo, Nicholas ; Teng, Linda ; Ashikari, Daisaku ; Porter, Laura H ; Simpson, Kaylene J ; Taylor, Renea A ; Goode, David L ; Ramm, Susanne ; Risbridger, Gail P ; Lawrence, Mitchell G ; Niranjan, Birunthi

AbstractThere are diverse phenotypes of castration‐resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co‐expressed in AR‐positive and AR‐null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR‐positive and AR‐null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo. Collectively, these results show that epigenome‐targeted inhibitors cause decreased growth and phenotype‐dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

01 May 2024·Pharmacology & Therapeutics

Characteristics of anticancer activity of CBP/p300 inhibitors – Features of their classes, intracellular targets and future perspectives of their application in cancer treatment

Review

Author: Robaszkiewicz, Agnieszka ; Strachowska, Magdalena

Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity.

02 Oct 2023·Cancer research

Androgen Receptor Variants Confer Castration Resistance in Prostate Cancer by Counteracting Antiandrogen-Induced Ferroptosis.

Article

Author: Ye, Dingwei ; Pang, Jun ; Huang, Haojie ; Wang, Liguo ; Ding, Donglin ; Li, Hao ; Yan, Binyuan ; Sun, Rui

Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.SIGNIFICANCEUpregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.

100 Deals associated with NEO-2734

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Epigenetix	21 Dec 2022
Castration-Resistant Prostatic Cancer	Phase 1	US	Epigenetix	21 Dec 2022
Chronic Myelomonocytic Leukemia	Phase 1	US	Epigenetix	21 Dec 2022
Myelofibrosis	Phase 1	US	Epigenetix	21 Dec 2022
NUT midline carcinoma	Phase 1	US	Epigenetix	21 Dec 2022
Diffuse Large B-Cell Lymphoma	Preclinical	-	Epigene Labs SASStartup	-
Diffuse Large B-Cell Lymphoma	Preclinical	-	Neomed Institute	-
Leukemia	Preclinical	-	Neomed Institute	-
Prostatic Cancer	Preclinical	-	Epigene Labs SASStartup	-
Prostatic Cancer	Preclinical	-	Neomed Institute	-

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