Advancements in Thrombocytopenia Therapy: The Development and Potential of SB-497115 as a TPO Receptor Agonist

Thrombopoietin (TPO), a 332-amino-acid cytokine, is crucial in controlling the development of megakaryocytes and platelet formation. In the last decade, engineered versions of TPO have demonstrated efficacy in treating thrombocytopenias linked to chemotherapy and other conditions, albeit with the potential risk of neutralizing antibody development. A small molecule TPO receptor agonist presents a safer alternative with benefits such as reduced production costs and the possibility of oral administration. TPO's mechanism involves receptor oligomerization and activation of signaling proteins like JAK1/JAK2 kinases and STAT transcription factors.

A high-throughput assay using STAT-activated reporter genes in BAF-3/TPO-R cells identified diazo naphthalenesulfonic acids from a 260,000 compound library as new TPO-R agonists. Structural modifications led to the creation of hydrazino naphthalenesulfonates, which showed comparable efficacy to TPO in cell-based assays, including a luciferase reporter gene and proliferation in a TPO receptor-dependent manner. These compounds also induced similar signal-transduction responses to TPO, such as JAK2 and STAT-5 activation, and promoted differentiation of megakaryocytes in human bone marrow cultures. The most potent compounds had EC50 values between 10-100 nM but lacked oral bioavailability due to their polar sulfonic acid groups.

Molecular modeling guided the development of biphenyl carboxylates, which showed favorable pharmacokinetic profiles, including oral bioavailability. Among over 200 analogs, SB-497115 was chosen for clinical trials due to its optimal biological and pharmacokinetic properties. It demonstrated full efficacy in BAF-3/TPO-R cell proliferation (EC50 = 30 nM) and increased CD41+ cells, indicating megakaryocyte differentiation (EC50 = 100 nM). Oral bioavailability in rats, dogs, and monkeys was 26%, 83%, and 89%, respectively.

SB-497115, a TPO mimetic with a molecular weight of 442, validates the use of JAK/STAT-based assays for drug discovery. It is the first small, non-peptidyl molecule shown to selectively activate a cytokine receptor, as evidenced by increased platelet counts in human volunteers during Phase I clinical trials. Ongoing evaluations are assessing SB-497115's potential in treating human thrombocytopenia.