Ownership: Astex

Mechanism of Action: Antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP) (T-cell Lymphomas)

Indication: T-cell Lymphomas

How this therapy can help

Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). Apoptosis or programmed cell death, while part of normal cell behavior, is often altered in cancer cells and can be prevented by overexpression of anti-apoptotic proteins, such as XIAP and cIAP. These IAPs are key regulators of anti-apoptotic and pro-survival signaling pathways and their dysregulation, through overexpression or loss of endogenous antagonists, occurs in various cancers. This is associated with tumor growth, poor prognosis and resistance to treatment, making IAPs attractive targets for anticancer therapy.

Tolinapant has a unique IAP antagonist molecular profile and has been shown to exert its activity through both IAP antagonism and via an immune-related mechanism. Given the importance of XIAP in regulating both extrinsic and intrinsic apoptosis pathways, improved XIAP antagonism, as demonstrated with tolinapant compared to other IAP antagonists in the clinic, has the potential to result in enhanced pro-apoptotic activity and tumor cell death.

Clinical status

Tolinapant is currently being evaluated in patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma as part of the Phase 2 portion of a Phase 1/2 study in patients with advanced solid tumors and lymphomas to determine safety, pharmacokinetics and preliminary activity.

Tolinapant is also being studied in combination with oral decitabine and cedazuridine in the treatment of acute myeloid leukemia (AML). Tolinapant is currently being developed by Taiho Oncology Inc. which also has an exclusive right to commercialize the drug in the USA.

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