**1. Introduction**

About 95% of the pancreatic ductal adenocarcinoma (PDAC) originates in the exocrine pancreas, and 5% is generated in the endocrine pancreas. There are several precursors for the development of PDAC; among them, noninfiltrating lesions, called pancreatic intraepithelial neoplasia or PanIN [1], are remarkable. The followup of the PanIN toward an infiltrating lesion is given by the abnormal distribution inside the pancreas. These lesions can be located in the pancreatic parenchyma, which causes its infiltration. Currently, the development of a pancreatic adenocarcinoma is monitored by measuring the overexpression of EGFR, KRAS, MUC1, and MUC4 genes or the inactivation of INK4A, TP53, and BRCA2 genes, which are essential for proper cell functioning [1–4, 5–8].

The invasive ductal adenocarcinoma is the most common pancreatic neoplasm, as it occurs in 85% of the cases. Eighty percent of the patients with this type of neoplasm have an average survival of 3–6 months after the detection; that is why this adenocarcinoma has been proposed as one of the most deadly existing [1, 9–11]. The invasive micro ductal adenocarcinoma deforms the small pancreatic glands, infiltrates the stroma, and triggers a fibrous coating, where 98% of the cases present mutations in the KRas4B gene [2, 10]. One of the most important factors for the development, maintenance, and progression of this disease is the presence of mutations in the KRas4B oncoprotein, which is mutated in 99% of PDAC cases [12]. Kras4B is a small GTPase, which belongs to the RAS protein subfamily, and it has essential functions in the control and regulation of normal cell proliferation. Human tumors almost always express mutated KRas4B proteins, from 90 to 99% of cases; specific mutations of this protein occur in codons 12, 13, or 61, which leaves the KRas4B protein constitutively active [11]. The active state of KRas4B proteins contributes significantly to develop the malignant phenotype, such as the deregulation of tumor cell growth, the evasion of programmed cell death, invasion, and angiogenesis [13]. There are three genes that code for RAS proteins in the mammalian genome: HRas, NRas, and KRas; four isoforms are obtained by alternative splicing: H-Ras, N-Ras, K-Ras4A, and K-Ras4B [14].

RAS subfamily proteins are also members of a broad class of proteins known as CAAX proteins [15] like this because the C-terminal end sequence has the CAAX amino acids (C: cysteine, A: aliphatic amino acid, and X: any amino acid), and this sequence is modified post-translationally in order to confer Ras protein affinity for the plasma membrane (for its subsequent activation). This process is regulated by three enzymes that work sequentially: first, the farnesyltransferase enzyme participates in the prenylation of the CAAX sequence; second, a protein called Rasconverting enzyme (RCE1) cleaves the last two amino acids of the CAAX sequence; third, a methyltransferase (ICMT) allows adding a methyl group to the carboxyl of the cysteine terminal to finally generate the mature RTP GTPase [16]. Farnesylation in the 185 cysteine terminal allows Ras proteins to increase their affinity for cell membranes and for many farnesyl group binding proteins that are analogous to RhoGDI transporters, such as phosphodiesterase 6 delta subunit (PDE6δ), which has been described as an indispensable molecule in the traffic of some GTPases of the Ras family [14, 17]. After the findings about the presence of KRas4B and its importance in the formation, maintenance, and progression of the most deadly neoplasms such as the PDAC [18, 19], studies have been conducted to discover and develop pharmacological inhibitors against oncogenic KRas4B. The approaches include: (a) finding small molecules that interact with KRas4B directly in order to prevent its activation [18, 19]; (b) finding enzyme inhibitors responsible for the post-translational modifications in order to prevent the transport of KRas4B to the

*KRas4BG12C/D/PDE6δ Heterodimeric Molecular Complex: A Target Molecular Multicomplex… DOI: http://dx.doi.org/10.5772/intechopen.93402*

plasma membrane; (c) finding compounds that inhibit the KRas4B downstream signaling pathway, as well as autophagy inhibitors and inhibitors of neoplastic cell metabolism [18, 19].

Despite the enormous prevalence of Kras4B mutations in pancreatic cancer, an efficient targeted treatment against aberrant signaling of this oncoprotein has not been found. It is known that pancreatic cancer cells with mutated Kras4B exhibit a phenomenon called "oncogene addiction", in which their survival becomes dependent on Kras4B signaling. Therefore, the inhibition of the Kras4B function promotes the inhibition of the viability of cancer cells; this eventually leads to cell death by apoptosis and the regression of the tumor [20, 21]. Therefore, it is necessary to find new strategies that allow us to inhibit the molecular mechanisms of activation and/or signaling of mutated Kras4B in pancreatic cancer. In this chapter, we describe new organic molecules that inhibit the dissociation of the heterodimeric molecular complex KRas4BG12C-D/PDE6δ; thus promoting that KRas4BG12C/D cannot bind to the plasma membrane, and consequently, it cannot be activated in pancreatic tumor cells.
