AbstractObjectivesTwo promising epigenetic therapeutic targets have emerged for the treatment of hematologic malignancies, BET and CBP/EP300 proteins. Several studies have shown that targeting these individual classes of proteins has anti‐tumor activity in multiple myeloma (MM), as well as other cancers. Here, we present the first data exploring the anti‐tumor activity of two novel dual inhibitors, NEO2734 and NEO1132, of both BET and CBP/EP300 proteins in MM.MethodsSixteen MM cell lines (MMCLs) were treated with the dual inhibitors NEO2734 and NEO1132, the single BET inhibitors JQ1, OTX015, IBET‐762, and IBET‐151, and a single CBP/EP300 inhibitor CPI‐637.ResultsThe dual inhibitor NEO2734 showed strong anti‐tumor activity and was consistently highly active against all MMCLs, being as potent as JQ1 and more so than other single inhibitors. NEO2734 and NEO11132 induced a significant G1 cell cycle arrest and decreased c‐MYC and IRF4 protein levels in MMCLs compared to the other single inhibitors. Sensitivity to the dual inhibitors was not dependent on a specific MM molecular subgroup but correlated with c‐MYC protein expression levels.ConclusionsThe dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.

1993-01-01·Infectious Complications in Bone Marrow Transplantation

Late Bacterial Infections in Humoral Immune Deficiency

Review

作者: Tutschka, P J

Between 2 and 3 months after allogeneic marrow transplantation, once past the hurdles of acute GVHD, opportunistic viral infections, and fungal and bacterial superinfections, the cellular immune system is slowly progressing toward full immunocompetence, a process that will not be completed until close to 2 years after transplantation when finally delayed-type hypersensitivity response is normalized. Equally, T helper function for B cell production of immunoglobulins starts to return, normal immunoglobulin levels being reached not before 4 months after transplantation (Atkinson 1990b; Lum 1987). This state of relative calm can be interrupted by an important complication of allogeneic bone marrow transplantation, chronic graft-versus-host disease which, as more and more patients survive the early post-transplant complications, is becoming an ever-increasing problem (Atkinson 1990a). This syndrome, a chronic, severe and often relentlessly progressing complication, now affects more than half of the transplanted patients and is associated with a number of distinct immunobiological features. Clinically chronic GVHD resembles autoimmune diseases and most often includes a Sjogren’s syndrome with xerophthalmia and xerostomia, poikiloderma and cutaneous sclerosis, and hepatic dysfunction with features of cholestasis.

HemaSphere

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells

Article

作者: van der Deure, Tiem ; Martiañez Canales, Tania ; Giles, Francis ; Vermue, Eline ; Ossenkoppele, Gert J. ; Smit, Linda ; van Gils, Noortje ; Denkers, Fedor ; Rutten, Arjo

Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.

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适应症	最高研发状态	国家/地区	公司	日期
弥漫性大B细胞淋巴瘤	临床前	-	Biomodal Ltd.	-
弥漫性大B细胞淋巴瘤	临床前	-	Neomed Institute	-
白血病	临床前	-	Neomed Institute	-
前列腺癌	临床前	-	Neomed Institute	-