Anticancer agent - talabostat
The process of blood cell formation, haematopoiesis, is modulated by cytokines.
The process of blood cell formation, haematopoiesis, is modulated by cytokines.
Stem cells are transformed into intermediate progenitor cells, and these are then turned into mature blood cells by progressive differentiation. A number of serine proteases are thought to play a role in regulating the haematopoeitic activity of the cytokines. Aminoborine dipeptides are transition state analogues for the catalytic site of a number of serine proteases, and may be able to regulate cytokine production in the haematopoiesis process by inhibiting the activity of dipeptidyl peptidase.
US company Point Therapeutics is developing talabostat, also referred to as PT-100, a small molecule that is orally active and stimulates the growth of primitive progenitor cells.1,2 It does this by causing an increase in the production of several growth factors that are needed to induce haematopoesis. It is being developed as a cancer treatment for a variety of different tumour types, and also to treat diseases such as anaemia, thrombocytopenia and neutropoenia, which involve the disruption of normal haematopoetic processes.
An initial dose escalation study was carried out to establish its safety and effects on neutrophil recovery in patients being treated with chemotherapy regimes that cause myelosuppression.3 A total of 29 patients were given 200, 400, 800 or 1200µg twice a day in their second cycle of chemotherapy. The best response was seen in those given 800µg doses, with the neutropoenia in five of the 13 patients being improved for at least two days. The drug was generally well tolerated; the most frequently seen adverse events were oedema and peripheral swelling, hypovolaemia and hypotension. The maximum tolerable dose was not reached. Most patients experienced and upregulation in G-CSF, IL-6 and IL-8.
Phase II trials are under way for a number of anticancer indications, including as monotherapy in lymphocytic leukaemia, metastatic melanoma and non-small cell lung cancer, as well as the aforementioned chemotherapy-induced haematopoetic disorders. It is also being investigated in combination with rituxumab to treat non-Hodgkin's lymphoma.