Compound AB8939 is a structurally novel, small chemical molecule, synthesized tubulin inhibitor that can circumvent P-glycoprotein (Pgp) and myeloperoxidase (MPO) mediated resistance, thereby conferring an important advantage over traditional tubulin inhibitors.
AB8939 is initially being developed in acute myeloid leukemia (AML) because cancer cells proliferate rapidly in this disease. AB8939 is 100 times more potent than doxorubicin (adriamycin), which is a reference drug in AML. Furthermore, AB8939 is not deactivated by myeloperoxidase enzyme, which is an advantage over vinca alkaloids (vincristine or vinblastine).
The aim of AB Science with compound AB8939 has been to design an ultra-selective small-molecule drug, having strong antiproliferative properties and an acceptable safety profile with minimal cardiac or neuronal toxicity.
The therapeutic potential of AB8939 in AML was demonstrated using cytarabine (Ara-C) resistant and azacitidine resistant patient-derived xenograft (PDX) models. Ara-C is considered the clinically most relevant cytotoxic agent for AML treatment, while azacitidine is a widely used hypomethylating agent for AML1, 2, 3.
AB8939 substantially decreased the concentration of blasts in blood (38d post-graft), bone marrow (BM) and spleen (52d post-graft) relative to azacitidine (Vidaza®), a widely used hypomethylating agent for AML.
Therapeutic potential of AB8939 in AML demonstrated in vivo using an Ara-C resistant PDX model. Single agent AB8939 significantly decreased the concentration of blasts in blood and bone marrow (41d post-graft), and decreased tumor growth relative to Ara-C.
- Humbert M, et al. (2019). Anticancer Activity of a Highly Potent Small Molecule Tubulin Polymerization Inhibitor, AB8939. Blood. 134. 2075-2075. 10.1182/blood-2019-122540.
- Goubard A, et al. (2019). In Vivo Assessment of the Next Generation Microtubule-Destabilizing Agent AB8939 in Patient-Derived Xenograft Models of Acute Myeloid Leukemia. Blood. 134. 5142-5142. 10.1182/blood-2019-127143.
- Goubard A, et al. (2019). AB8939, a Microtubule-Destabilizing Agent with Potential to Overcome Multidrug Resistance, Is Active across the Range (M0-M7) of Acute Myeloid Leukemia Subtypes. Blood. 134. 5154-5154. 10.1182/blood-2019-127021.