- |||||||||| inobrodib (CCS1477) / CellCentric
Activity of Orally Available CBP/p300 Degraders in Pre-Clinical Models of Multiple Myeloma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5214;
Some compounds, including inobrodib, have progressed to early-stage clinical trials...With intermittent dosing strategies, advanced compounds lead to potent and sustained loss of CBP and p300 in myeloma cell lines and tumor xenografts and achieve tumor reduction as single agents when delivered orally. With these optimized compounds, we can now address systematically (in vitro and in vivo) the relative consequences of CBP/p300 inhibition and degradation both in tumor cells and normal tissue/hematopoietic cells.
- |||||||||| Crebbp Inhibition Potentiates JAK2 Inhibition in Post-MPN Acute Myeloid Leukemia (Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_2072;
Here, we demonstrate through genome-wide CRISPR screens in post-MPN AML line HEL treated with four different JAK2 inhibitors (i.e. ruxolitinib, momelotinib, pacritinib and fedratinib) that depletion of CREBBP sensitizes cells to JAK2 inhibition...In both human and murine models of post-MPN AML, the combination treatment of ruxolitinib plus CREBBP/EP300 inhibitor SGC-CBP30 or CCS1477 substantially induced apoptosis and cell cycle arrest at G1...Overall, our results demonstrate that CREBBP/EP300 inhibition potentiates JAK2 inhibition in post-MPN AML by further attenuating MYC expression and activity, and repressing JAK/STAT and other pathways associated with JAK2 inhibitor persistence. Therefore, we propose CREBBP inhibition as a potential therapeutic strategy to potentiate JAK2 inhibition in post-MPN AML.
- |||||||||| Next-Generation Novel Therapies in Multiple Myeloma (Room D (1F)) - Sep 24, 2024 - Abstract #ICBMT2024ICBMT_137;
A wealth of therapeutic options have been approved for the treatment of newly diagnosed (ND) and relapsed/refractory (RR) multiple myeloma (MM) over the past two decades, with proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), and monoclonal antibodies (mAbs; including the CD38 mAbs daratumumab and isatuximab, as well as the SLAMF7-targeting mAb elotuzumab) currently forming the backbone of treatment approaches in each setting. Additional targeted therapies have further enhanced the armamentarium, including, previously, the histone deacetylase inhibitor panobinostat, and, more recently, the nuclear export inhibitor selinexor 1 and the peptide
- |||||||||| inobrodib (CCS1477) / CellCentric
Trial completion date, Trial primary completion date, Monotherapy: Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - Jul 17, 2024
P1/2, N=350, Recruiting,
Additional targeted therapies have further enhanced the armamentarium, including, previously, the histone deacetylase inhibitor panobinostat, and, more recently, the nuclear export inhibitor selinexor 1 and the peptide Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024
- |||||||||| inobrodib (CCS1477) / CellCentric
Preclinical, Journal: Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity. (Pubmed Central) - Apr 23, 2024
Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477...14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.
- |||||||||| NEO2734 / Epigenetix, inobrodib (CCS1477) / CellCentric
Review, Journal: Characteristics of anticancer activity of CBP/p300 inhibitors - Features of their classes, intracellular targets and future perspectives of their application in cancer treatment. (Pubmed Central) - Apr 15, 2024
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.
- |||||||||| inobrodib (CCS1477) / CellCentric
Targeting the CBP/p300 axis in lethal prostate cancer impacts DNA repair (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_9347;
In this study, CBP/p300 mediated bromodomain activity is targeted by CCS1477 (inobrodib), a first-in-class bromodomain inhibitor developed by Cell Centric...These collective findings reveal that CBP/p300 govern repair of DNA DSBs by regulating HR, thus modulating genome integrity and promoting CRPC growth. These studies identify CBP/p300 as a driver of PCa tumorigenesis through coordinated control of critical transcriptional events and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed therapies.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, inobrodib (CCS1477) / CellCentric
Genetic or pharmacological inactivation of CREBBP sensitizes B-cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition (Section 15) - Mar 5, 2024 - Abstract #AACR2024AACR_2877;
Lastly, we demonstrate that small-molecule inhibition of CREBBP sensitizes B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in vitro and in vivo, providing a potential novel drug combination for broader clinical translation in B-ALL. In summary, we have identified a number of actionable compounds that specifically target CREBBP-mutated high-risk B-ALL, demonstrate a novel mechanism-of-action for the BCL2 inhibitor Venetoclax in B-ALL and propose CREBBP-inhibitors and Venetoclax as a novel treatment combination for B-ALL across genotypes.
- |||||||||| inobrodib (CCS1477) / CellCentric
Journal: Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma. (Pubmed Central) - Feb 23, 2024
Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182...Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.
- |||||||||| inobrodib (CCS1477) / CellCentric
Histone Acetyltransferase P300/CBP in Pulmonary Arterial Hypertension and Associated Right Ventricular Failure (Zone 4, Science and Technology Hall, Level 2) - Oct 12, 2023 - Abstract #AHA2023AHA_8490;
In addition, P300/CBP inhibition prevents phenylephrine-induced hypertrophy in H9C2 cells and adult rat cardiomyocytes (IF, p<0.05). In vivo, administration of CCS-1477 reduces pulmonary vascular remodeling (Elastica Van Gieson, p<0.05), improves pulmonary hemodynamics (p<0.01) and attenuates RV fibrosis (Masson's Trichrome, p<0.05) in MCT rats with established PAH.CONCLUSION We provide evidence that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH.
- |||||||||| inobrodib (CCS1477) / CellCentric
Trial completion date, Trial primary completion date, Monotherapy, Metastases: CCS1477-02: Study to Evaluate CCS1477 in Haematological Malignancies (clinicaltrials.gov) - Oct 11, 2023
P1/2, N=250, Recruiting,
In vivo, administration of CCS-1477 reduces pulmonary vascular remodeling (Elastica Van Gieson, p<0.05), improves pulmonary hemodynamics (p<0.01) and attenuates RV fibrosis (Masson's Trichrome, p<0.05) in MCT rats with established PAH.CONCLUSION We provide evidence that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH. Trial completion date: Mar 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Jun 2025
- |||||||||| inobrodib (CCS1477) / CellCentric
Potent pre-clinical activity of EP300/CBP bromodomain inhibitor CCS1477 in multiple myeloma (In Person) - Sep 10, 2023 - Abstract #IMW2023IMW_464;
P1/2
CCS1477 treatment rapidly alters EP300/CBP chromatin occupancy and subsequent gene expression programs, resulting in potent anti-tumour activity in multiple myeloma cells. These encouraging data provide a strong rationale for the ongoing phase I/IIa clinical trial investigating the safety and efficacy of CCS1477 in advanced haematological malignancies (NCT04068597), and provide mechanistic insight into the activity of CCS1477 against multiple myeloma.
- |||||||||| JQ-1 / Roche, inobrodib (CCS1477) / CellCentric
Group 3 medulloblastoma transcriptional networks are selectively sensitive to EP300 and CBP bromodomain inhibition (Section 20; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_8409;
Mechanistically, treatment of MB cells with CCS1477, but not A-485 or the BRD4 inhibitor JQ1, caused rapid early loss of mRNA expression of specific G3MB dependency networks including the driver oncogene c-MYC. These studies identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB cells and provide new chemical approaches to disrupting malignant transcription in Group 3 medulloblastoma.
- |||||||||| inobrodib (CCS1477) / CellCentric
Targeting CBP/p300 and its downstream transcriptional machinery in advanced prostate cancer (Section 11; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_4083;
CCS1477 (inobrodib) is a first-in-class bromodomain inhibitor developed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival...In conclusion, these studies identify CBP/p300 as a driver of PCa tumorigenesis through coordinated control of critical transcriptional events and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed therapies. Combined, these studies have the capacity for significant near-term impact in the prevention and/or management of metastatic disease.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, inobrodib (CCS1477) / CellCentric
Therapeutic Targeting of EP300/CBP By Bromodomain Inhibition in Acute Myeloid Leukemia (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5755;
P1/2
Azacitidine and CCS1477 in particular demonstrated synergistic growth inhibitory activity in the MOLM16 model, as did venetoclax in MOLM16 and MV(4;11) models. These encouraging pre-clinical and early phase clinical findings set the stage for the clinical trial evaluation of CCS1477 in combination with azacitidine and venetoclax.
- |||||||||| inobrodib (CCS1477) / CellCentric
Potent Pre-Clinical and Early Phase Clinical Activity of EP300/CBP Bromodomain Inhibitor CCS1477 in Multiple Myeloma (ENMCC - New Orleans Theater C) - Nov 4, 2022 - Abstract #ASH2022ASH_1411;
P1/2
Finally, we evaluated the activity of CCS1477 in an OPM-2 xenograft model in combination with existing standard of care agents in myeloma and observed additive or synergistic growth inhibitory activity with each of bortezomib, lenalidomide and vorinostat in combination with CCS1477. These encouraging data suggest strong promise for the clinical utility of CCS1477 in the treatment of multiple myeloma as monotherapy and/or in combination with standard of care agents.
- |||||||||| inobrodib (CCS1477) / CellCentric
Enrollment change, Trial completion date, Trial primary completion date, Monotherapy: Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - Jul 5, 2022
P1/2, N=350, Recruiting,
BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials. N=200 --> 350 | Trial completion date: Jun 2022 --> Mar 2024 | Trial primary completion date: Jun 2022 --> Mar 2024
- |||||||||| inobrodib (CCS1477) / CellCentric
Enrollment change, Monotherapy, Metastases: CCS1477-02: Study to Evaluate CCS1477 in Haematological Malignancies (clinicaltrials.gov) - Jul 5, 2022
P1/2, N=250, Recruiting,
N=200 --> 350 | Trial completion date: Jun 2022 --> Mar 2024 | Trial primary completion date: Jun 2022 --> Mar 2024 N=90 --> 250
- |||||||||| inobrodib (CCS1477) / CellCentric
Journal: Targeting p300/CBP axis in lethal prostate cancer. (Pubmed Central) - Jan 29, 2022
Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced PC.
- |||||||||| inobrodib (CCS1477) / CellCentric
Trial completion date, Trial primary completion date, Monotherapy: Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - Jan 21, 2022
P1/2, N=200, Recruiting,
Overall, CCS1477 shows promise for the treatment of patients with advanced PC. Trial completion date: Dec 2021 --> Jun 2022 | Trial primary completion date: Dec 2021 --> Jun 2022
- |||||||||| inobrodib (CCS1477) / CellCentric
Trial completion date, Trial primary completion date, Monotherapy, Metastases: CCS1477-02: Study to Evaluate CCS1477 in Haematological Malignancies (clinicaltrials.gov) - Jan 21, 2022
P1/2, N=90, Recruiting,
Trial completion date: Dec 2021 --> Jun 2022 | Trial primary completion date: Dec 2021 --> Jun 2022 Trial completion date: Dec 2021 --> Mar 2024 | Trial primary completion date: Dec 2021 --> Mar 2024
- |||||||||| CCS1477 / CellCentric
Journal: Toppling the HAT to Treat Lethal Prostate Cancer. (Pubmed Central) - Oct 9, 2021
In this issue of Cancer Discovery, Welti and colleagues demonstrate a positive correlation between the expression of the histone acetyltransferase paralogs CBP and p300 with increased androgen receptor (AR) signaling and androgen deprivation therapy resistance in advanced prostate cancer. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer.See related article by Welti et al., p. 1118.
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