Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

Abstract

KRAS‒PDE δ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDE δ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDE δ inhibitors with potent antitumor activity both in vitro and in vivo . In particular, compound 36l ( K D = 127 ± 16 nmol/L) effectively bound to PDE δ and interfered with KRAS–PDE δ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDE δ interaction.

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

“…For instance, farnesyl-transferase inhibitors that block the enzyme-mediating Ras farnesylation are now applied with some success in HRAS mutant head and neck cancers . While some PDE6Di were shown to dislodge K-Ras more or less from the plasma membrane within 60–90 min, ,,, only in some cases was evidence for a moderate effect on Ras signaling provided. ,, Nevertheless, all of these PDE6Di demonstrated cell killing activity in KRAS mutant pancreatic or colorectal cancer cells; however, these are assays that cannot detect off-target activities.…”

“…22,23 Interestingly, in their most recent work, their spirocyclic compound 36l (K D = 127 nM) showed target engagement in cells while also demonstrating in vivo efficacy against KRAS mutant primary cell linederived xenografts. 24 In another study, compounds around a triazole scaffold were developed, of which compound 27 had nanomolar activity in a PDE6D binding assay and robustly inhibited MAPK output at 10 μM and A549 cell growth at this concentration range. 25 Another PDE6Di emerged from a Rac-inhibitor screen, which led to the oxadiazole DW0254 as a submicromolar active compound (K D = 436 ± 6 nM).…”

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

“…Additionally, it is the most effective small molecule inhibitor of KRAS-PDE δ reported to date, suggesting its potential as a therapeutic agent for the treatment of pancreatic cancer. 355 …”

“…Additionally, it is the most effective small molecule inhibitor of KRAS-PDEδ reported to date, suggesting its potential as a therapeutic agent for the treatment of pancreatic cancer. 355 Bcl-2 PPI inhibitors Bcl-2 family plays a crucial role in the endogenous apoptosis signal transduction pathway by regulating the mitochondrial/cytochrome C-mediated apoptosis process. 356,357 This family consists of anti-apoptotic and pro-apoptotic proteins that act synergistically as apoptotic switches, ultimately determining the cell's fate.…”

Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC)

“…The oncogenic function of KRAS proteins depends on their localization and enrichment in the cell membranes, and PDEδ plays a key role in the transfer of KRAS from the cytosol to the cell membrane. Therefore, KRAS-PDEδ protein–protein interaction (PPI) has become an emerging target in pancreatic cancer. , In recent years, a number of small molecule KRAS-PDEδ inhibitors have been reported (Figure C), such as compound 3 and deltazinone ( 4 ). − Our group also identified several potent PDEδ inhibitors with low nanomolar affinity. − Although these inhibitors effectively blocked the KRAS-PDEδ PPI, they were limited by poor antitumor activity due to the rapid release of inhibitors from PDEδ induced by endogenous Arl2 . Thus, it is critical to develop novel strategies that target PDEδ more effectively.…”