Abstract LB423: Preclinical profiling of CY002-243-1: A highly potent PDE3A-SLFN12 molecular glue for cancer therapy

Abstract Introduction: Phosphodiesterase (PDE) is a superfamily of enzymes that mediates the hydrolysis of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), regulates the concentration of cAMP and cGMP in cells. cAMP and cGMP-mediated second messenger signaling pathways are involved in regulating multiple functions of cells. Therefore, PDE can affect and regulate diverse physiological processes by regulating the activity of cAMP and cGMP, including cell proliferation and apoptosis, inflammatory response, contraction of cardiomyocytes and smooth muscle cells, permeability of endothelial cells, et al. Recent studies have shown that multiple compounds with distinct chemotypes such as anagrelide, DNMDP, and nauclefine can induce the formation of PDE3A-SLFN12 complexes in a fashion of molecular glue. On the one hand, the formation of the complex stabilizes the protein level of intracellular SLFN12 (regularly, SLFN12 is degraded through the ubiquitination pathway, maintaining a relatively low intracellular level). The PDE3A-SLFN12 complex can bind to the downstream ribosomal RNA (rRNA), blocking the binding of SRP (signal recognition particle) to ribosomes. On the other hand, binding of PDE3A-SLFN12 to rRNA leads to a decrease in the protein levels of the anti-apoptotic proteins Bcl-2 and Mcl-1, making them unable to inhibit the activity of Bax and Bak. The oligomerization of Bax and Bak further promoted the increase of mitochondrial membrane permeability, initated the release of cytochromes, and induced apoptosis in tumor cells. Herein, we presented a novel molecular glue CY002-243-1, which mainly induced apoptosis of tumor cells through the PDE3A-SLFN12 complex, while avoiding the toxicity and side risks caused by the inhibition of PDE3A enzyme activity. Results: CY002-243-1 demonstrated potent antiproliferative activity across a panel of cancer cells (Melanoma, NSCLC, Endometrial, Esophageal, Hepatocellular, Ovarian, IC50 ranged from 0.02∼2.9 nM, ∼100-fold more potent than BAY2666605 and Anagreilde). In the SK-MEL-3 Melanoma tumor xenograft model, administration of HP-001 (0.1 mpk, QD) promoted tumor regression (∼95% tumor growth inhibition by 14 days), compared to ∼90% tumor growth inhibition by 14 days in BAY2666605 (1 mpk, QD) group. Cardiovascular safety was thoroughly examined since the enhanced efficacy of CY002-243-1 could be attributed to the improvement on PDE3A-binding. The Langendorff isolated heart perfusion experiment was conducted to confirm the ex-vivo effect of compounds with ranged PDE3A inhibition activity, CY002-243-1 demonstrated no significant positive inotropic action. To further confirm the inhibition activity on the ion channels, hERG/ hNav1.5/hCav1.2 tests were conducted on BAY2666605 and CY002-243-1. With no significant effect on the above ion channels and 10x lower minimal effective in-vivo exposure, CY002-243-1 demonstrated superior ion channel safety profile compared to BAY2666605. Conclusions: CY002-243-1 is a highly potent, PDE3A-SLFN12 molecular glue, with marked anti-tumor activity as a single agent across diverse tumor cell. Citation Format: Dihuang Wang, Jinhua Wu, Zheng Xu, Liwei Deng, Liwen Zhao. Preclinical profiling of CY002-243-1: A highly potent PDE3A-SLFN12 molecular glue for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB423.