Using Insights into Pim1 Structure to Design New Anticancer Drugs

Abstract

Human Pim1 (proviral integration site for Moloney murine leukemia virus) kinase is a 313-amino acid serine-threonine kinase that possesses several biological functions in cell survival, proliferation and differentiation, and its overexpression has been observed in a number of human cancers. Indeed, this kinase is a proto-oncogene that has been implicated in early transformation and tumor progression, especially in hematopoietic malignancies and prostate carcinoma where it is a marker of a poor prognosis. For these reasons, Pim1 is emerging as an important target in drug discovery, and many Pim1 inhibitors have been reported in the last three years. The challenge of this research is to obtain compounds that specifically inhibit only Pim1 and not Pim2 and Pim3, the other members of the Pim family, with the aim of providing selective inhibitors as potential therapeutic agents and also of studying the different roles of the three enzymes. In this review Pim1 functions and Pim1 role in human cancer are summarized, but the primary focus of the article is on the Pim1 three-dimensional structure that was deeply analyzed by a detailed inspection of the available crystallographic data and all complexes of small molecule inhibitors reported in the literature to this point. Finally, the use of molecular modeling techniques for the identification and optimization of Pim1 inhibitors is extensively discussed. This data collection, which to the best of our knowledge was not previously reviewed in such detail, could offer a useful tool for medicinal chemists working in the field of small molecule kinase inhibitors.

Insights from Pim1 structure for anti-cancer drug design

“…When the distance threshold is set to 4.5 Å , the ATP-mimetic inhibitor BIM-1 (PDB code: 1XWS, Figure 3A), the ATPcompetitive inhibitor K00135 (PDB code: 2C3I, Figure 3B), the phenylpyrimidine analog (PDB code: 3DCV, Figure 3D), the hydroxybenzofuran derivative I (PDB code: 3UMX, Figure 4A) and the quinazoline derivative (PDB code: 3UIX, Figure 4C) interact with various residues, including Leu44, Gly45, Phe49, Val52, Ala65, Lys67, Ile104, Leu120, Glu121, Arg122, Val126, Asp128, Glu171, Leu174, Ile185 and Asp186, as summarized in Table 3. Schenone et al [57] also reported that more than 60% of 25 inhibitors analyzed interacted with Leu44, Val52, Ala65, Ile104, Leu120, Leu174 and Ile185.…”

“…X-ray structural analyses revealed the presence of an extensive network of a salt bridge (Arg166--Asp200) and hydrophobic interactions (Leu164, Leu193, Tyr198 and Phe201) between the A-loop and the C-loop, and the hydrogen bonds (Leu192-Tyr198, Lys194-Val197) inside the A-loop are crucial for opening the ATP binding pocket and stabilizing the active conformation [52]. The structures of the ATP binding pockets in protein kinases are quite similar, and thus the development of a highly selective drug is difficult [55][56][57]. Protein kinases commonly form two hydrogen bonds with the ATP adenine through the residues in the hinge region, while Pim1 forms only one hydrogen bond, between the N6 atom of the ATP adenine ring and the backbone carbonyl oxygen atom of the first hinge residue (Glu121) ( Figure 2B) [50][51][52].…”

Bcr-Abl tyrosine kinase inhibitors: a patent review

“…They are particularly active on the proviral integration site for Moloney murine leukemia virus (PIM) kinases, which are involved in the development of different tumors [67]. However, some derivatives demonstrate a good activity on Bcr-Abl T315I, and in particular compounds 31a --c ( Figure 10) show IC 50 values of 0.07, 0.03 and 0.07 mM, respectively.…”

3,5-Bis(aminopyrimidinyl)indole Derivatives: Synthesis and Evaluation of Pim Kinase Inhibitory Activities

“…5,9 Pim family consists of structurally homologous members with Pim-1 and Pim-2 sharing 61% similarity while Pim-1 and Pim-3 having 71% similarity at the amino acid level. 2 This offers a unique opportunity to generate highly specific small molecule inhibitors against all three pim kinases.…”