Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors

Jiao, Xiaojin; Kopecky, David J.; Liu, Jinsong; Liu, Jinqian; Jaén, Juan C.; Cardozo, Mario; Sharma, Rajiv; Walker, Nigel; Wesche, Holger; Li, Shyun; Farrelly, Ellyn; Xiao, Shou‐Hua; Wang, Zhong Lin; Kayser, Frank

doi:10.1016/j.bmcl.2012.08.020

Cited by 58 publications

(47 citation statements)

References 26 publications

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“…This loop is not present in some of the structures deposited in the PDB database, which might reflect a certain degree of flexibility. Nonetheless, PDB entry 4ewh presents the active state of the kinase including this loop region (23), in which the side chain of D163 is solvent exposed and may be involved in the dimerization interface (Figure 3A). In the interface, however, no potentially interacting residue, that would engage the aspartate carboxyl group in either an ionic interaction (Lys/Arg) or a hydrogen bond (Ser/Thr), could be found in the near proximity (<5Å).…”

Section: Resultsmentioning

confidence: 99%

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Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis

et al. 2016

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The amount of genomic information about leukemia cells currently far exceeds our overall understanding of the precise genetic events that ultimately drive disease development and progression. Effective implementation of personalized medicine will require tools to distinguish actionable genetic alterations within the complex genetic landscape of leukemia. In this study, we performed kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Deep sequencing of the same patient specimens identified genetic alterations that were then integrated with the functionally important targets using the HitWalker algorithm to prioritize the mutant genes that most likely explain the observed drug sensitivity patterns. Through this process, we identified Tyrosine Kinase Non-receptor 2 (TNK2) point mutations that exhibited oncogenic capacity. Importantly, the integration of functional and genomic data using HitWalker allowed for prioritization of rare oncogenic mutations that may have been missed through genomic analysis alone. These mutations were sensitive to the multi-kinase inhibitor dasatinib, which antagonizes TNK2 kinase activity, as well as novel TNK2 inhibitors, XMD8-87 and XMD16-5, with greater target specificity. We also identified activating truncation mutations in other tumor types that were sensitive to XMD8-87 and XMD16-5, exemplifying the potential utility of these compounds across tumor types dependent on TNK2. Collectively, our findings highlight a more sensitive approach for identifying actionable genomic lesions that may be infrequently mutated or overlooked, and provide a new method for the prioritization of candidate genetic mutations.

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Section: Resultsmentioning

confidence: 99%

“…In a different approach, comparison of the active and inactive conformation of the TNK2 kinase domain reveals the classical rearrangements within the N-lobe (Figure 3B) (20,23). Specifically, in the inactive state, the αC-helix undergoes an outward movement and also the N-terminal β-sheet is repositioned.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis

et al. 2016

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“…A large number of substituents were introduced at the para-position of the 6-phenyl ring, significant improvements in both biochemical and cellular ACK1 led to the identification of potent and selective dithiolane inhibitor (Compound 22) with good kinase selectivity, and a suitable in vitro metabolic profile ( Figure 5). Unfortunately, the pharmacokinetic profile of this was poor and prevented this inhibitor from being further evaluated in tumor xenograft studies 87 .…”

Section: Ack1mentioning

confidence: 99%

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

Adel

Serya

Lasheen

et al. 2018

Journal of Advanced Pharmacy Research

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Pyrrolopyrimidine derivatives comprise a class of biologically active heterocyclic compounds that are well known to play a critical role in pharmaceutical drug design and health care. The pyrrolopyrimidines serve as promising scaffolds that were found in a number of biologically active compounds including antibiotics, anti-inflammatory, anti-viral and anticancer. Researchers were inspired to develop novel pyrrolopyrimidine derivatives for the treatment of Cancer. Currently several pyrrolopyrimidines are available commercially as anticancer drugs. The present review article offers a detailed account on the development of pyrrolopyrimidine derivatives with anticancer potential with emphasis on their activity as targeted kinase inhibitors.

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“…Recently, high throughput screen of small molecule compounds unveiled two new classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines [53]. Although Compound 6, a furanopyrimidine potently inhibited ACK1 activity in vitro (K i =70 nM), its ability to inhibit ACK1 in vivo was observed to be less impressive (cell IC 50 of 5.6 uM).…”

Section: Ack1 Inhibitorsmentioning

confidence: 99%

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

Mahajan

2013

Cancer Letters

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ACK1 tyrosine kinase, located on chromosome 3q29, is aberrantly activated, amplified or mutated in a wide variety of human cancers. While the deregulated kinase is oncogenic and its activation correlates with progression to metastatic stage, its inhibition causes cell cycle arrest, sensitizes cells to ionizing radiation and induces apoptosis. Oncogenicity of ACK1 is not only due to its ability to promote activation of critical pro-survival kinases and receptors by phosphorylating at distinct tyrosine residues, but also by employing a similar mechanism to eliminate a tumor suppressor from cancer cells. Despite the substantial data supporting the oncogenic role of ACK1, and the potential clinical benefit of blocking ACK1 in metastatic disease, to date ACK1-specific small molecule inhibitors have not been exploited for cancer therapy. This review highlights recent advances that elucidate how cancer cells employ ACK1 kinase to their advantage and discusses some of the novel ACK1 inhibitors that have shown promise in pre-clinical studies.

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Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors

Cited by 58 publications

References 26 publications

Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis

Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

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