P3, N=740, Not yet recruiting, Tempest Therapeutics | Trial completion date: Dec 2029 --> Jul 2030 | Initiation date: Mar 2025 --> Dec 2025 | Trial primary completion date: Mar 2028 --> Dec 2028

PPARα antagonists, such as N-(2-bromophenyl)-2-[[(3-chlorophenyl)amino]thioxomethyl]acetamide (GW6471) and TPST-1120, impair tumor metabolism and angiogenesis, reducing cancer progression...This review provides a comprehensive analysis of the medicinal chemistry, molecular mechanisms, and pharmacological development of PPAR antagonists, highlighting their potential clinical applications. Future efforts should refine drug design, develop personalized treatments, and conduct well-designed clinical trials to unlock their role in precision oncology.

P3, N=740, Not yet recruiting, Tempest Therapeutics

Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.

TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers.

There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001.

P1, N=38, Completed, Tempest Therapeutics | Active, not recruiting --> Completed | N=138 --> 38 | Trial completion date: Jun 2024 --> Sep 2022

TPST-1120 was well tolerated and showed signs of activity in a phase I trial as monotherapy and in combination with nivolumab (NCT03829436). TPST-1120 treated patients with PR demonstrated fatty acid oxidation perturbations and immune gene expression changes as potential biomarkers of clinical benefit. Increased frequencies of responding patients bearing PI3K pathway or IDH mutations may reveal populations likely to benefit from treatment with TPST-1120. 1.

Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.

Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.

On examining the substrate interaction status of AEDs with BCRP, VPA, phenytoin and lamotrigine were found to be potential BCRP substrates...Significance Statement Induction of multidrug transporters at blood-brain barrier can largely affect the bioavailability of the substrate antiepileptic drugs in the brains of patients with epilepsy, thus affecting their therapeutic efficacy. The present study reports a mechanistic pathway of breast cancer resistance protein (BCRP/ABCG2) upregulation by valproic acid in human brain endothelial cells via peroxisome proliferator-activated receptor alpha involvement, thereby providing a potential strategy to prevent valproic acid pharmacoresistance in epilepsy.

Trial Registration TPST-1120 as Monotherapy and in Combination With Nivolumab in Subjects With Advanced Cancers (NCT03829436). Patients with PR demonstrated gene expression changes that implicate immune activation and alleviation of immune suppression as potential biomarkers of clinical benefit. Increased frequencies of responding patients bearing PI3K pathway or IDH mutations may reveal populations likely to benefit from treatment with TPST-1120.