Drug Interaction Study with Healthy Subjects
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: Merck Sharp & Dohme LLC
No Placebo Group
Trial Summary
What is the purpose of this trial?Researchers have designed a study medicine called bomedemstat (MK-3543) as a new way to treat certain rare blood diseases.
The purpose of this study is to learn what happens to bomedemstat in a person's body over time (a pharmacokinetic or PK study). Researchers will compare what happens to bomedemstat in the body when it is given alone and after multiple doses of another medicine called carbamazepine (CBZ).
What safety data is available for Bomedemstat and related treatments?
Bomedemstat (IMG-7289) is a lysine-specific demethylase 1 (LSD1) inhibitor that has been evaluated in clinical trials for its potential as an anticancer treatment. The study titled 'Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology' mentions that Bomedemstat is among the new chemical entities that have reached clinical trials in oncology. However, the study does not provide specific safety data for Bomedemstat. The research primarily focuses on the characterization of LSD1 inhibitors, including Bomedemstat, in terms of their potency and selectivity as potential anticancer treatments. Therefore, while Bomedemstat has been studied in clinical trials, specific safety data from these trials is not detailed in the provided research.
13567Is the drug Bomedemstat a promising treatment?
Bomedemstat is a promising drug because it targets LSD1, an enzyme linked to cancer growth. It has shown potential in treating various cancers by disrupting cancer cell processes and promoting cell differentiation. Bomedemstat is one of several LSD1 inhibitors that have reached clinical trials, indicating its potential as an effective cancer treatment.
23678What data supports the idea that the drug is an effective treatment?
The available research shows that Bomedemstat (IMG-7289) is being studied as a potential treatment for various cancers. It is part of a group of drugs called LSD1 inhibitors, which are being tested for their ability to treat different types of cancer, including blood cancers and solid tumors. Although the research highlights that another drug, iadademstat, is the most potent among similar drugs, Bomedemstat is still considered a promising candidate and has entered clinical trials. This suggests that it has shown some effectiveness in early studies, but more research is needed to fully understand its potential.
34568Do I have to stop taking my current medications for the trial?
Yes, you must stop taking all drugs, including prescription and non-prescription medications, herbal remedies, or vitamin supplements, starting 14 days before entering the study.
Eligibility Criteria
This trial is for healthy adults with no significant medical history, who haven't smoked or used nicotine products in the last 3 months. Participants should have a BMI between 18.0 and 32.0 kg/m2.Participant Groups
The study is testing bomedemstat, a new potential treatment for rare blood diseases, to see how it behaves in the body over time alone and when taken with carbamazepine, another medication.
1Treatment groups
Experimental Treatment
Group I: Bomedemstat + CarbamazepineExperimental Treatment2 Interventions
A single dose of bomedemstat will be administered On Day 1 of Period 1. There will be a washout of 7 days between bomedemstat dosing in Period 1 and the first carbamazepine (CBZ) dose in Period 2. In Period 2, CBZ will be administered twice daily (BID) for 17 consecutive days, with a single dose of bomedemstat coadministered with the morning dose on Day 14.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Celerion, Inc. ( Site 0001)Tempe, AZ
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Who is running the clinical trial?
Merck Sharp & Dohme LLCLead Sponsor
References
CD86 expression as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase lysine-specific demethylase 1. [2017]There is a lack of rapid cell-based assays that read out enzymatic inhibition of the histone demethylase LSD1 (lysine-specific demethylase 1). Through transcriptome analysis of human acute myeloid leukemia THP1 cells treated with a tranylcypromine-derivative inhibitor of LSD1 active in the low nanomolar range, we identified the cell surface marker CD86 as a sensitive surrogate biomarker of LSD1 inhibition. Within 24h of enzyme inhibition, there was substantial and dose-dependent up-regulation of CD86 expression, as detected by quantitative polymerase chain reaction, flow cytometry, and enzyme-linked immunosorbent assay. Thus, the use of CD86 expression may facilitate screening of compounds with putative LSD1 inhibitory activities in cellular assays.
Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors. [2017]Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1.
LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models. [2022]Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7.
Identification of selective and reversible LSD1 inhibitors with anti-metastasis activity by high-throughput docking. [2020]The overexpression of lysine specific demethylase 1 (LSD1) has been reported in various human tumors. There is increasing interest in targeting LSD1 with small molecules for cancer treatment. A released structure of an LSD1 kinase domain in complex with FAD was used to set up a low-cost high-throughput docking protocol for quick identification of LSD1 inhibitors. The most promising hit L05 was confirmed to be a potent, selective and reversible LSD1 inhibitor and displayed marked inhibition of colorectal cells migration without significant cytotoxicity.
First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. [2021]Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML).
Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. [2022]Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles. [2023]Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (trans-2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silico hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10) showed the most desirable activities, and its eutomer, S1427, was isolated by the optical resolution of 10. In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.
Recent advances of LSD1/KDM1A inhibitors for disease therapy. [2023]Lysine-specific demethylase 1 (LSD1/KDM1A) dysregulation is closely associated with the pathological processes of various diseases, especially hematologic malignancies. Significant progresses have been made in the field of LSD1-targeted drug discovery. Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. This review updates LSD1 inhibitors reported during 2022. Design strategies, structure-activity relationship studies, binding model analysis and modes of action are highlighted. In particular, the unique multiple-copies binding mode of quinazoline derivatives paves new ways for the development of reversible LSD1 inhibitors by blocking the substrate entrance. The design strategy of clinical candidate TAK-418 also provides directions for further optimization of novel irreversible LSD1 inhibitors with low hematological side effects. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given.