At Imago, our research is focused on therapeutics that can change the behavior of malignant blood cells through targeting lysine-specific demethylase 1 (LSD1): an enzyme that controls how genes are turned ‘on’ and ‘off’ in specific cells. LSD1 plays an essential role in the step-wise maturation of cells in the bone marrow. LSD1 plays a unique role in each step of blood cell formation and function.
Epigenetics is the mechanism by which gene expression is regulated through chemical modifications of proteins, RNA and DNA, without altering the underlying DNA sequence. Epigenetic modifications to the DNA itself or a class of proteins known as histones may attract or repel the molecular machinery responsible for turning on and off gene expression, or transcription.
While epigenetic processes are required for normal development, the disruption of these cellular activities can lead to altered gene expression and ultimately malignant cellular transformation. The connection between epigenetics and cancer was initially established by research that identified abnormal DNA modification that disrupted normal gene expression, promoting uncontrolled cell division. Other academic research in which thousands of different cancer cell genomes have been sequenced, identified mutations in many genes coding for epigenetic proteins. These mutations lead to the loss of regulation of the normally tight cellular control on growth and differentiation.
Imago is focused on an epigenetic enzyme, LSD1, one of over 100 known epigenetic proteins, that plays a central role in the production of cells in the bone marrow. LSD1 regulates the proliferation of blood stem cells and is essential for the differentiation of the cells responsible for platelet production, called megakaryocytes, and immune cells called granulocytes.
In essential thrombocythemia, excess megakaryocyte results in too many platelets that can cause blood to clot. In myelofibrosis, excess megakaryocyte activity gives rise to inflammatory cytokines and growth factors that damages the bone marrow, making blood production progressively more difficult. While LSD1 is very rarely mutated in cancer, elevated levels of wild-type LSD1 are common in many blood cancers and solid tumors and are correlated with poor prognosis in high-risk prostate and breast cancer.
Given the critical role that LSD1 plays in the function of malignant blood cells, targeting LSD1 offers a new mechanism for the treatment of blood cancers associated with high morbidity and mortality. The significant unmet need of patients and their families dealing with these high-risk disorders is what has driven us to develop internally discovered, novel inhibitors and degraders of LSD1. By advancing drug candidate products that inhibit LSD1, we hope to improve and prolong the lives of patients with cancer and bone marrow diseases.
We are using this scientific foundation to advance our internally discovered lead product candidate, bomedemstat, for the treatment of myeloproliferative neoplasms (MPNs): a family of related, chronic cancers of the bone marrow. Bomedemstat is an orally available, small molecule, inhibitor of LSD1. Currently, bomedemstat is being tested in clinical studies as a potentially disease-modifying monotherapy for essential thrombocythemia (ET), myelofibrosis (MF), polycythemia vera (PV) and potentially other indications.