iadademstat (ORY-1001)

This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat...In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.

These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.

While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

The differential prognosis of the mutation in various chromosomal and VAF settings will be explored. Lastly, we will outline therapeutic options, promising treatments on the horizon, and whether allogeneic stem cell transplant is curative.

P1, N=15, Not yet recruiting, Yale University

P2, N=20, Terminated, Fox Chase Cancer Center | N=42 --> 20 | Trial completion date: Aug 2026 --> Jul 2025 | Recruiting --> Terminated; Closed to accrual due to low probability of successful outcomes

We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents...These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. The full data sets are available on PubChem.

This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation.

P1, N=45, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Together, our results establish that the SE-RBBP7-LSD1 axis represents a potential therapeutic target for BCa treatment.

P1, N=45, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=12, Recruiting, Medical College of Wisconsin | Not yet recruiting --> Recruiting | Initiation date: Oct 2024 --> Jan 2025