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Our Science

 Illustration of body cells overlaying the back of a human body.
In advancing our lead programs, we are employing a unique dual-target approach to reprogram a key biological pathway called the CoREST complex.

Why Target CoREST?

CoREST (Co-repressor of Repressor Element-1 Silencing Transcription) is a complex of enzymes that play critical roles in regulating gene expression affecting multiple vital biological functions including hematopoiesis (the biological process of creating, developing, and replenishing blood components), neurogenesis (the generation of new nerve cells), and cancer. As a result, seeking out ways to correct dysfunction within this complex is proving to be of great interest to drug developers across an array of diseases, particularly serious blood disorders, neurodegenerative diseases, and oncology.

CoREST inhibitors currently in development include a range of candidates that act through a variety of mechanisms to modulate CoREST activity and influence gene expression and cellular functions. However, to date, clinical development efforts have largely focused on single‑target modulation of the CoREST complex. We believe that dual, integrated targeting may offer meaningful biological and clinical advantages.

 coREST diagram (mobile orientation)

Why Dual-Targeted Approach to the CoREST Complex

We are currently advancing our lead candidate through clinical development targeting two specific CoREST complex enzymes of interest: LSD1 (lysine-specific demethylase-1) and HDAC6 (histone deacetylase 6).

LSD1

LSD1 is an enzyme critical for the proliferation of blood stem cells and the self-renewal potential of malignant cells. Targeting LSD1 has proven useful clinically in the treatment of certain myeloproliferative neoplasms (MPNs), a group of rare, chronic blood cancers that can cause blood thickening, increased risk of thrombosis, and can lead to acute leukemia. Common MPNs include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Myelofibrosis (MF).

HDAC6

HDAC6 is a primarily cytoplasmic enzyme that acts as a master regulator of cell motility, protein trafficking, and modulation of immune responses. Overexpression of HDAC6 is seen in multiple cancer types and neurodegenerative disorders and has been shown to increase megakaryocyte differentiation and dysfunctional platelet production. We believe that selective inhibition of HDAC6 could therefore prove useful in the treatment of a wide range of diseases.

 By selectively and simultaneously targeting LSD1 and HDAC6 with a single, integrated small molecule, we aim to deliver precise epigenetic modulation with pharmacologic properties optimized for chronic disease management.

The Opportunity in Essential Thrombocythemia (ET)

Essential thrombocythemia (ET) is a rare, chronic blood condition that occurs when the bone marrow produces too many platelets, most often due to genetic mutations, including JAK2, CALR, or MPL. Elevated platelet and white blood cell counts both contribute to thrombotic risk in ET, underscoring the importance of therapies that address the underlying biology driving disease morbidity. ET affects an estimated 150,000 people in the U.S.
Essential Thrombocythemia (ET) process
ET is a myeloproliferative neoplasm characterized by excessive platelet production and, in some patients, elevated WBC counts

Dual LSD1/HDAC6 inhibition targets the 
 root biology and clinical consequences of ET

Dual LSD1/HDAC6 inhibition targets the root biology and clinical consequences of ET

Despite increased understanding of the disease, there have been no new treatments approved for ET in almost 30 years. Current treatments for ET include cytoreductive therapies such as hydroxyurea, Peg-IFN-α, and anagrelide, all of which leave significant room for improvement in both efficacy and tolerability.

Hydroxyurea

Hydroxyurea is used as a first-line treatment for high-risk patients, despite its lack of influence on underlying disease biology or mutations, development of resistance or intolerance, and long‑term use associated with cumulative toxicity and treatment‑limiting adverse effects.

Peg-IFN-α

Peg-IFN-α is used second-line to suppress megakaryocyte progenitors and normalize maturation; while it does reduce malignant clones, there is high discontinuation due to flu-like symptoms, CNS toxicity, frequent requirement of monitoring, and relatively slow onset of activity.

Anagrelide

Anagrelide is a second-line treatment option that has been shown to have higher rates of arterial thrombosis, bleeding, and discontinuation vs hydroxyurea, cardiovascular toxicity, increased bleeding risk, increased risk of myelofibrosis progression vs hydroxyurea, and no effect on underlying biology or mutations.

Additional Therapeutic Opportunities

We believe that employing this dual-mechanistic approach may have meaningful utility beyond ET and provide advantages over current treatments and other candidates in development.

Other Myeloproliferative Neoplasms (MPNs)

Primary Myelofibrosis (MF): a rare, chronic blood cancer where bone marrow is replaced with scar tissue, disrupting blood cell production. MF affects an estimated 18,000 people in the U.S., about half of whom do not respond to existing JAK inhibitors.

Polycythemia Vera (PV): a rare, slow-growing blood cancer where bone marrow produces too many red blood cells, causing thickening of the blood, and increased risk of blood clots, heart attack, and stroke. An estimated 165,000 people have PV in the U.S., with approximately 70% estimated to be high risk and 20% to be resistant to hydroxyurea.

 LSD1 inhibition has now been well validated as a therapeutic approach in essential thrombocythemia (ET) and other MPNs, with multiple agents demonstrating consistent effects on hematologic parameters and emerging signals of disease modification. However, as more fully described Science Advances, targeting LSD1 alone may be insufficient to fully disrupt CoREST‑driven biology, as the system depends on multi-component and non‑catalytic interactions. JBI‑802 was designed with this in mind, combining LSD1 inhibition with HDAC6 to extend beyond the CoREST complex and target complementary regulatory pathways such as JAK‑STAT signaling, enabling a more complete and potentially durable biological response. Read Moreabout this scientific advance

Click below to learn more about our lead clinical candidate JBI-802, a first-in-class dual LSD1/HDAC6 inhibitor that builds on validated LSD1 biology while extending beyond it.

Our Pipeline