Hit to lead evaluation of 1,2,3-triazolo[4,5-b]pyridines as PIM kinase inhibitors

Pastor, Joaquı́n; Oyarzábal, Julen; Saluste, Gustavo; Álvarez, Rosa; Rivero, Virginia; Ramos, Francisco; Cendón, Elena; Blanco‐Aparicio, Carmen; Ajenjo, Nuria; Cebriá, Antonio; Albarran, Maria I.; Cebrián, David; Corrionero, Ana; Fominaya, Jesús; Montoya, Guillermo; Mazzorana, Marco

doi:10.1016/j.bmcl.2011.12.130

Cited by 40 publications

(18 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further studies involving this chemical series validated the in silico chemogenomics profiling (details below) and the structure-based VS approach as prospective tools. The docking studies fit perfectly with the experimental data (RMSD between the crystal structure and the corresponding docked molecule was 1.80 Å) maintaining all critical binding interactions described in Figure 5 [29].…”

Section: Resultssupporting

confidence: 63%

“…A detailed structure-relationship analysis (SAR) was obtained during the hit to lead evaluation process and has recently been published [29]. Additional work exploring other selected scaffolds will be reported in due course.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, based on the new series reported in this manuscript, the next step of the drug discovery process started: a medicinal chemistry project was launched to explore initial hits described below. Details about the corresponding hit explosion from the identified starting points have recently been published [29].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors

et al. 2012

Self Cite

View full text Add to dashboard Cite

A new chemical series, triazolo[4,5-b]pyridines, has been identified as an inhibitor of PIM-1 by a chemotype hopping strategy based on a chemically feasible fragment database. In this case, structure-based virtual screening and in silico chemogenomics provide added value to the previously reported strategy of prioritizing among proposed novel scaffolds. Pairwise comparison between compound 3, recently discontinued from Phase I clinical trials, and molecule 8, bearing the selected novel scaffold, shows that the primary activities are similar (IC50 in the 20 to 150 nM range). At the same time, some ADME properties (for example, an increase of more than 45% in metabolic stability in human liver microsomes) and the off-target selectivity (for example, an increase of more than 2 log units in IC50 vs. FLT3) are improved, and the intellectual property (IP) position is enhanced. The discovery of a reliable starting point that fulfills critical criteria for a plausible medicinal chemistry project is demonstrated in this prospective study.

show abstract

Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…This group includes imidazo[1,2- b ]pyridazine [24], the substituted pyridine [30], and triazolo[4,3- b ]pyridazine [34]. The SKI-O-068 chemical scaffold resembles the triazolopyridazine (PDB code 3BGQ; Ki ∼11 nM) [35] and triazolopyridine scaffolds (PDB code 4A7C; IC 50 ∼6 nM) [36] in the borderline group (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of Pim1 Kinase in Complex with a Pyrido[4,3-D]Pyrimidine Derivative Suggests a Unique Binding Mode

et al. 2013

View full text Add to dashboard Cite

Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor.

show abstract

“…SGI-1776 inhibits Pim kinases (K i = 12, 980 and 20 nM for Pim-1, Pim-2 and Pim-3, respectively) [122][123][124][125] and demonstrated anticancer efficacy against multiple tumor models [123,126]. As the second-generation Pim inhibitor, SGI-9481 was designed to improve potency and toxicology profile compared with SGI-1776.…”

Section: Design Of Pim Inhibitorsmentioning

confidence: 99%

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

Kumarasiri

Adams

et al. 2015

Future Med. Chem.

View full text Add to dashboard Cite

Pim oncogenes are highly expressed in many types of hematological and solid cancers. Pim kinases regulate the network of signaling pathways that are critical for tumorigenesis and development, making Pim kinases the attractive drug targets. Currently, two approaches have been employed in designing Pim kinase inhibitors: ATP-mimetics and non-ATP mimetics; but all target the ATP-binding pocket and are ATP-competitive. In this review, we summarize the current progress in understanding the Pim-related structure and biology, and provide insights into the binding modes of some prototypical Pim-1 inhibitors. The challenges as well as opportunities are highlighted for development of Pim kinase inhibitors as potential anticancer agents.

show abstract

Hit to lead evaluation of 1,2,3-triazolo[4,5-b]pyridines as PIM kinase inhibitors

Cited by 40 publications

References 23 publications

Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors

Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors

Crystal Structure of Pim1 Kinase in Complex with a Pyrido[4,3-D]Pyrimidine Derivative Suggests a Unique Binding Mode

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

Contact Info

Product

Resources

About