sirpiglenastat (DRP-104)

P2, N=37, Recruiting, NYU Langone Health

Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity...To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.

While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2029 --> Sep 2033

This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2027 --> Aug 2029 | Trial primary completion date: Feb 2027 --> Aug 2028

Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.

Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1b/2 --> P1/2

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting