KRas4BG12C/D/PDE6δ Heterodimeric Molecular Complex: A Target Molecular Multicomplex for the Identification and Evaluation of Nontoxic Pharmacological Compounds for the Treatment of Pancreatic Cancer

Abstract

The search for new targeted therapies to improve the quality of life of patients with pancreatic cancer has taken about 30 years. Compounds that can inhibit the K-Ras4B oncoprotein signaling pathway have been sought. Taking into account that the interaction of KRas4B with PDE6δ is essential for its transport and subsequent activation in the plasma membrane, our working group identified and evaluated in vitro and in vivo small organic molecules that could act as molecular staples to stabilize the KRas4B/PDE6δ heterodimeric complex. From this group of molecules, 38 compounds with high interaction energies on the structure of the crystallized molecular complex were selected, indicating that they efficiently stabilized the molecular complex. In vitro evaluation of compounds called D14, C22, and C19 showed significant specific effects on the cell viability of pancreatic cancer cells (and not on normal cells), thus inducing death by apoptosis and significantly inhibiting the activation of the pathways, signaling AKT and ERK. In addition to these experimental findings, we were also able to detect that compounds D14 and C22 showed significant tumor growth inhibitory activity in pancreatic cancer cellinduced subcutaneous xenograft models.

Perspective Chapter: Evaluating New Drugs against K-Ras4B/PDE6δ Using an In Vitro Approach

“…Based on this, a series of compounds capable of binding and firmly fixing the interaction between the K-Ras and PDE6𝛿 proteins were selected in silico (Figure 2) [17]. These molecules showed excellent results against KRAS-dependent cancers, with elevated affinity towards mutated variants of K-Ras, thereby preserving the signaling activity of K-Ras WT [8,[18][19][20]. After several assays carried out in a big library of compounds, the molecules denominated as C14 and P8 showed the best ability to specifically bind to and stabilize the mutated K-Ras4B/PDE6δ complex (Figure 2) [17].…”

Controlled-Release Nanosystems with a Dual Function of Targeted Therapy and Radiotherapy in Colorectal Cancer

“…In the treatment of colorectal cancer, small molecules have been identified as inhibitors of different types of proteins that play an important role in signaling pathways that promote cancer progression. The small molecule C19 inhibits the viability and proliferation of colorectal cancer cells in vitro and in vivo, through decreased activation of KRAS and, therefore, inhibition of phosphorylation of downstream kinases such as AKT and ERK [ 77 , 78 , 79 ]. In this sense, C19 has also been used for administration in pancreatic cancer via a PAMAM nanoparticle system for the combined treatment of targeted chemoradiation therapy.…”