pulrodemstat (CC-90011) / BMS - LARVOL DELTA

Upregulation of SSTR2 expression and radioligand binding of [18F]SiTATE in neuroendocrine tumour cells with combined inhibition of class I HDACs and LSD1. (PubMed, Neuroendocrinology) - "Combined inhibition of class I HDACs and LSD1 potently increases SSTR2 expression and consequently radioligand binding and might thus be a putative strategy to improve the outcome of PRRT therapy in patients with NETs."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR • SSTR2

Pulrodemstat, a selective inhibitor of KDM1A, suppresses head and neck squamous cell carcinoma growth by triggering apoptosis. (PubMed, BMC Pharmacol Toxicol) - "Pulrodemstat is an effective therapeutic drug for HNSCC. Thus, the TET3/KDM1A axis may account for the malignant phenotype of HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • KDM1A

A Safety, Tolerability and Preliminary Efficacy Evaluation of CC-90011 Given in Combination With Cisplatin and Etoposide in Subjects With First Line, Extensive Stage Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=90 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates. (PubMed, Biochemistry) - "Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1."

Epigenetic controller • Journal • Acute Myelogenous Leukemia • Ewing Sarcoma • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Sarcoma • Small Cell Lung Cancer • Solid Tumor

A Safety, Tolerability and Preliminary Efficacy Evaluation of CC-90011 Given in Combination With Cisplatin and Etoposide in Subjects With First Line, Extensive Stage Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b ➔ P1 | Trial completion date: Feb 2024 ➔ Jun 2024 | Trial primary completion date: Feb 2024 ➔ Jun 2024

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

A Safety and Efficacy Study of CC-90011 in Participants With Relapsed and/or Refractory Solid Tumors and Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=75 | Terminated | Sponsor: Celgene | Trial completion date: Sep 2025 ➔ Mar 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2025 ➔ Mar 2024; Business objectives have changed

Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Repression of LSD1/KDM1A activity improves the response of liver cancer cells to the lenvatinib. (PubMed, Discov Oncol) - "Pulrodemstat synergized with Lenvatinib based on suppression of PI3K-AKT signaling and activation of apoptotic signaling."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CASP3

A Safety and Efficacy Study of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers (clinicaltrials.gov) - P2 | N=92 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

Uncovering New Conformational States of the Substrate Binding Pocket of LSD1 Potential for Inhibitor Design via Funnel Metadynamics. (PubMed, J Phys Chem B) - "To investigate whether the substrate binding pocket is rigid or exhibits other representative conformations different from the crystal conformations that are feasible for designing new LSD1 inhibitors, we performed funnel metadynamics simulations to study the conformation dynamics of LSD1 in the binding process of two effective LSD1 inhibitors (CC-90011 and 6X0, CC-90011 undergoing clinical trials)...Besides, alternative optimal binding modes and prebinding modes for both inhibitors were also detected, which depicted that the key interactions changed along with the binding process. Our results should provide great help for LSD1 inhibitor design."

Journal • Oncology

A Safety and Efficacy Study of CC-90011 in Participants With Relapsed and/or Refractory Solid Tumors and Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=91 | Active, not recruiting | Sponsor: Celgene | Trial primary completion date: Aug 2023 ➔ Sep 2025

Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics. (PubMed, ACS Chem Biol) - "The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors."

Journal • Review • Oncology • SNAI1

A Safety, Tolerability and Preliminary Efficacy Evaluation of CC-90011 Given in Combination With Cisplatin and Etoposide in Subjects With First Line, Extensive Stage Small Cell Lung Cancer (clinicaltrials.gov) - P1b | N=90 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Jun 2024 ➔ Feb 2024 | Trial primary completion date: Sep 2023 ➔ Feb 2024

Combination therapy • Trial completion date • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor

Phase 2 Multicohort Study of CC-90011, a LSD1 Inhibitor, in Combination with Nivolumab in Patients with Advanced Lung Cancer (IASLC-WCLC 2023) - P2 | "Overall, clinical activity was limited in this pre-treated patient population. No new safety signals emerged, and CC-90011 was well-tolerated in combination with nivolumab. Select biomarker data will be presented."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Neuroendocrine Tumor • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia • KDM1A

A Study of CC-90011 and Comparators in Participants With Prostate Cancer (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed | N=10 ➔ 6 | Trial completion date: Mar 2025 ➔ May 2023

Enrollment change • Metastases • Trial completion • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma. (PubMed, Exp Hematol Oncol) - "The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • SDC1

Exploring LSD1 inhibition as a novel therapeutic strategy to overcome proteasome inhibitors resistance in multiple myeloma and other B-cell malignancies (EACR 2023) - "Introduction Despite the success of proteasome inhibitors (PIs), like carfilzomib (CFZ) and bortezomib (BTZ) in treating multiple myeloma (MM) and mantle cell lymphoma (MCL), innate and/or acquired resistance and toxic side effects remain major challenges for therapy menagment...Small-molecule LSD1 inhibitors, such as SP2509, SP2577, and CC-90011, triggered synergistic cytotoxicity in combination with different PIs in MM and other B-cell tumors...We found that DNA damage and cell cycle checkpoint signaling were the most affected pathways by CFZ/SP2509 combined treatment.ConclusionThe present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might also be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project. Further studies are needed to explore the clinical potential of this..."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • SDC1

A Safety and Efficacy Study of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers (clinicaltrials.gov) - P2 | N=92 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Apr 2023 ➔ Jan 2024 | Trial primary completion date: Apr 2023 ➔ Jan 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies. (PubMed, Cancer) - P1 | "The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies."

Clinical • Journal • Endocrine Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Thrombocytopenia • GRP-10

A Study of CC-90011 and Comparators in Participants With Prostate Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Celgene | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target. (AACR 2023) - "In GBM cell line U251, IC50 of S2172 was lower than that of other LSD1 inhibitors (IC50 10.5 μM, 29.5 μM, 11.0 μM treated with S2172, Ory-1001, and CC-90011, respectively). While S2172 had a strong effect in vitro, S2172 seemed unsuccessful in killing differentiated GBM cells in vivo. These data suggests that treatment of S2172 is less effective to differentiated GBM cells and this is consistent with previous report that LSD1 as a candidate therapeutic target in stem-like tumor propagating cells in GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MYC

Recent advances of LSD1/KDM1A inhibitors for disease therapy. (PubMed, Bioorg Chem) - "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. 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."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology

A Safety, Tolerability and Preliminary Efficacy Study of CC-90011 in Combination With Venetoclax and Azacitidine in R/R Acute Myeloid Leukemia and Treatment-naïve Participants Not Eligible for Intensive Therapy (clinicaltrials.gov) - P1/2 | N=1 | Terminated | Sponsor: Celgene | Completed ➔ Terminated; Business objectives have changed.

Combination therapy • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. (PubMed, Front Pharmacol) - "Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents."

Journal • Review • Acute Myelogenous Leukemia • Alzheimer's Disease • CNS Disorders • Esophageal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Mood Disorders • Oncology • Personality Disorder • Solid Tumor

A Study of CC-90011 and Comparators in Participants With Prostate Cancer (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: Celgene | Trial completion date: Aug 2024 ➔ Mar 2025 | Trial primary completion date: Nov 2022 ➔ Jul 2023

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR