Taselisib (development code: GDC-0032) is a small-molecule drug that was investigated as a targeted cancer therapy and, later, for the treatment of PIK3CA-related overgrowth spectrum (PROS) disorders. It is a selective inhibitor of class I phosphoinositide 3-kinase (PI3K), with particular activity against the p110α (PIK3CA), p110δ, and p110γ isoforms, while sparing the p110β isoform.
Mechanism of Action Taselisib is an orally bioavailable inhibitor of the class I PI3K alpha isoform (PIK3CA). By selectively inhibiting PIK3CA and its mutant forms in the PI3K/Akt/mTOR signaling pathway, it can induce tumor cell apoptosis and growth inhibition in PIK3CA-expressing tumor cells. Dysregulation of the PI3K/Akt/mTOR pathway is a frequent event in human cancers, often driven by activating mutations in the PIK3CA gene.
Clinical Development in Oncology Taselisib was developed by Roche/Genentech primarily for the treatment of breast cancer. It was evaluated in the Phase III SANDPIPER study, a randomized trial assessing taselisib in combination with fulvestrant versus placebo plus fulvestrant in patients with estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. In June 2018, Roche announced that further development of taselisib would be discontinued following the top-line results of the SANDPIPER study, as the benefit-risk profile did not support continued development.
Research in Overgrowth Syndromes Taselisib was later investigated in the TOTEM trial (a Phase IB/IIA multicenter, open-label, single-arm study) for adult patients with PROS conditions such as CLOVES syndrome and Klippel–Trenaunay syndrome (KTS). In this trial, low-dose taselisib (1–2 mg daily) was evaluated for safety and efficacy. While 76.4% of participants reported some clinical improvement (including pain reduction and functional improvement), the study was terminated early due to dose-limiting toxicities (enteritis and pachymeningitis), and no significant reduction in affected tissue volume was observed. The authors concluded that the safety profile of low-dose taselisib precluded its long-term use.
Chemical Properties
- Molecular formula: C₂₄H₂₈N₈O₂
- CAS-type identifier (PubChem CID): 51001932
- It is a small-molecule, selective PI3K inhibitor.
