# Developing small molecule inhibitors of Pleckstrin-2 to treat thrombosis

> **NIH NIH R44** · APLEXIS, INC. · 2024 · $1,101,337

## Abstract

PROJECT SUMMARY
Thrombosis, often at unusual sites such as splanchnic vein and arteries, is a common complication and one of
the leading causes of mortality and morbidity in patients with myeloproliferative neoplasms (MPNs).
Developing effective therapies for thrombosis in MPNs is in its infancy. Current first-line therapy of chronic
phase MPNs includes aspirin, hydroxyurea, interferon a, or anagrelide. However, these treatment approaches
remain suboptimal with ongoing risks for thrombosis, hemorrhage, and impaired quality of life. Targeted
molecular therapy in this stage of MPNs for thrombosis is also lacking. Aplexis, Inc is a startup company
focusing on the development of new approaches to treat thrombosis in the chronic phase of MPNs, especially
targeting the downstream effectors of the JAK2 pathway that is commonly activated in these disorders. One of
these effectors is Pleckstrin-2 (Plek2) that is a novel target of the JAK2-STAT5 pathway. Previous studies have
shown that loss of Plek2 ameliorated JAK2V617F mutant-induced myeloproliferative phenotypes, and reverted
thrombosis and lethality of the JAK2V617F MPN mouse model. Importantly, Plek2 is overexpressed in the bone
marrow and peripheral blood mononuclear cells from JAK2V617F positive chronic MPN patients. Given the
significance of Plek2 in thrombosis pathogenesis in MPNs, Aplexis has been collaborating with Ji laboratory at
Northwestern University and has identified hit compounds of Plek2 small molecule inhibitors using in silico-
based high-throughput screening and cell-based assays. With the support of the Phase I SBIR grant, Aplexis
achieved another milestone by developing a lead compound APX-052 with potent efficacies and safety
profiles. Mechanistic studies further revealed that APX-052 binds to Plek2 and disrupts Plek2-Akt interaction,
which reduces Akt activation and inhibits cell proliferation. The goal of this Phase II SBIR project is to
determine the toxicity and pharmacokinetics of APX-052 and test it in various in vivo MPN models. We will also
initiate IND-enabling studies and conduct a pre-IND briefing with FDA. Aplexis has a strong support from
Northwestern University’s Innovation and New Ventures Office (INVO) on an exclusive license for the
associated patent-pending intellectual property from this technology. The collaboration with the Ji laboratory at
Northwestern University will ensure the success of the proposed research, which will position Aplexis to the
next step in the production of clinical candidate of Plek2 inhibitors.

## Key facts

- **NIH application ID:** 10819880
- **Project number:** 2R44HL165997-02
- **Recipient organization:** APLEXIS, INC.
- **Principal Investigator:** Jing Yang
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,101,337
- **Award type:** 2
- **Project period:** 2022-09-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819880

## Citation

> US National Institutes of Health, RePORTER application 10819880, Developing small molecule inhibitors of Pleckstrin-2 to treat thrombosis (2R44HL165997-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10819880. Licensed CC0.

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