Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma

Hollebecque, Antoine; Salvagni, Stefania; Plummer, Ruth; Isambert, Nicolás; Niccoli, Patricia; Capdevila, Jaume; Curigliano, Giuseppe; Moreno, Víctor; Martín-Romano, Patricia; Baudin, Éric; Arias, Marina; Mora, Sheila; Alvaro, Juan de; Martino, Jorge Di; Parra-Palau, Josep Lluís; Sánchez-Pérez, Tania; Aronchik, Ida; Filvaroff, Ellen; Lamba, Manisha; Nikolova, Zariana; Bono, Johann S. de

doi:10.1158/1078-0432.ccr-20-2380

Cited by 31 publications

(30 citation statements)

References 44 publications

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“…Thrombocytopenia and neutropenia events are consistent with the target biology and were indeed reported for this compound in monotherapy. 83,84 Bomedemstat, a notably less potent irreversible LSD1 inhibitor, is being explored in essential thrombocythemia and myelofibrosis (MF). The Phase II doses (40−60 mg/day) are about 500-fold higher than iadademstat, exceeding the 10 mg/ day threshold managed commonly in the risk assessment for idiosyncratic toxicity of covalent binders and increasing the risk for off-target activities.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Pulrodemstat is currently being tested in five trials in AML, Non-Hodgkin’s lymphomas, and prostate and small cell lung cancers, alone or in different combinations and regimens. Preliminary data showed encouraging antitumor activity and favorable tolerability in patients with unresectable solid tumors and relapsed and/or refractory Non-Hodgkin’s lymphoma . Cyclopropylamine compounds like iadademstat irreversibly inactivate LSD1 by generating an adduct with the FAD cofactor, ,, whereas pulrodemstat resides reversibly in the active site cavity .…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

Sacilotto

Dessanti

Lufino

et al. 2021

ACS Pharmacol. Transl. Sci.

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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.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

Sacilotto

Dessanti

Lufino

et al. 2021

ACS Pharmacol. Transl. Sci.

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“…e efforts to regain the sensitivity of available chemotherapeutic drugs and subdue resistance of drug of tumor cells are still ongoing [52]. LSD1 is linked with multiple tumor types, and its expression in various tumors is linked with chemoresistance [53][54][55]. Epithelial-mesenchymal transition (EMT) plays a vital role in the chemoresistance of bladder cancer.…”

Section: Chemoresistance and Lsd1mentioning

confidence: 99%

LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor

Agboyibor

Dong

Effah

et al. 2021

Journal of Oncology

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Tumors are the foremost cause of death worldwide. As a result of that, there has been a significant enhancement in the investigation, treatment methods, and good maintenance practices on cancer. However, the sensitivity and specificity of a lot of tumor biomarkers are not adequate. Hence, it is of inordinate significance to ascertain novel biomarkers to forecast the prognosis and therapy targets for tumors. This review characterized LSD1 as a biomarker in different tumors. LSD1 inhibitors in clinical trials were also discussed. The recent pattern advocates that LSD1 is engaged at sauce chromatin zones linking with complexes of multi-protein having an exact DNA-binding transcription factor, establishing LSD1 as a favorable epigenetic target, and also gives a large selection of therapeutic targets to treat different tumors. This review sturdily backing the oncogenic probable of LSD1 in different tumors indicated that LSD1 levels can be used to monitor and identify different tumors and can be a useful biomarker of progression and fair diagnosis in tumor patients. The clinical trials showed that inhibitors of LSD1 have growing evidence of clinical efficacy which is very encouraging and promising. However, for some of the inhibitors such as GSK2879552, though selective, potent, and effective, its disease control was poor as the rate of adverse events (AEs) was high in tumor patients causing clinical trial termination, and continuation could not be supported by the risk-benefit profile. Therefore, we propose that, to attain excellent clinical results of inhibitors of LSD1, much attention is required in designing appropriate dosing regimens, developing in-depth in vitro/in vivo mechanistic works of LSD1 inhibitors, and developing inhibitors of LSD1 that are reversible, safe, potent, and selective which may offer safer profiles.

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“…The reversible KDM1A inhibitor CC-90011 has been found to induce cellular differentiation exhibits anti-tumor efficacy in vitro and in vivo in AML and SCLC ( Kanouni et al, 2020 ). CC-90011 was also tested in patients with hematological cancers, showing robust anti-cancer properties and good tolerability in patients ( Hollebecque et al, 2021 ). Currently, CC-90011 is being tested in clinical trials in patients with prostate and SCLC ( Table 2 ).…”

Section: Kdm Inhibitorsmentioning

confidence: 99%

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

2021

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Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as “erasers” which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology.

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Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma

Abstract: Supplementary tables/figures: 2/4 = 6 (no max.) References: 45 (50 max.) Research.

Cited by 31 publications

References 44 publications

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

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