Aptose Biosciences announces publication of preclinical data on tuspetinib

Aptose Biosciences (APTO) announced the publication of preclinical data for Aptose’s lead hematology compound tuspetinib in Cancer Research Communications. The publication, entitled “Preclinical development of tuspetinib for the treatment of acute myeloid leukemia,” is the first preclinical profiling of tuspetinib, a well-tolerated, once daily, oral kinase inhibitor currently in clinical development for treatment of acute myeloid leukemia. The publication defines TUS activities on select oncogenic signaling targets, demonstrates enhanced activity and safety of TUS when combined with other agents, and illustrates synthetic lethality when combined with venetoclax. Pharmacokinetic and toxicology studies revealed that TUS is readily absorbed and achieves plasma concentrations sufficient to inhibit the target kinases, it has a plasma half-life that supports once daily dosing, and it demonstrates a favorable safety profile. Aptose is now enrolling newly diagnosed AML patients in a Phase 1/2 clinical study to receive the tuspetinib + venetoclax + azacitidine triplet combination. Clinical studies in patients with relapsed or refractory AML receiving TUS single agent or the TUS+VEN combination have been completed. Key findings: Tuspetinib inhibits a defined cluster of oncogenic signaling kinases operative in AML; TUS inhibits SYK, JAK1/2, RSK2, mutant KIT, and wild type and mutant forms of FLT3; TUS potently killed AML lines and Ba/F3 cells expressing wildtype or various mutant forms of FLT3; TUS dampens stroma-induced activation of FLT3-ITD signaling in AML cells; TUS prolongs survival in multiple AML models; Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3 mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax or 5-azacytidine; TUS combines effectively with other classes of agents to kill AML cells with mutations in RAS and other difficult-to-treat adverse mutations; TUS was 2.1-15-fold and a 4.5-13-fold more potent than gilteritinib at blocking fibrinogen and immunoglobulin-mediated activation of SYK in KG-1a cells; The most notable observation was the marked and unexpected synthetic lethal vulnerability to venetoclax and two MCL1 inhibitors in the TUS-resistant cells.