Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity

Kaspersen, Svein Jacob; Han, Jin; Nørsett, Kristin G.; Rydså, Line; Kjøbli, Eli; Bugge, Steffen; Bjørkøy, Geir; Sundby, Eirik; Hoff, Bård Helge

doi:10.1016/j.ejps.2014.04.011

Cited by 25 publications

(28 citation statements)

References 53 publications

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“…For this class of drug candidates ADMET data is available as input for drug developmental programs [16][17][18]. We have focused our development on chiral benzylamine based pyrrolo [2,3-d]pyrimidines as EGFR inhibitors [19][20][21]. Only three pyrroloyrimidines based EGFR inhibitors have reached clinical trials, namely PKI-166 [22], AEE-788 [23,24], and TAK-285 [25,26], see Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

Han

Henriksen

Nørsett

et al. 2016

European Journal of Medicinal Chemistry

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The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFR reporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3-amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases.

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Section: Introductionmentioning

confidence: 99%

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

Han

Henriksen

Nørsett

et al. 2016

European Journal of Medicinal Chemistry

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“…These compounds were further evaluated towards a panel of 52 kinases revealing interesting Src-family kinase inhibitory activity. cpd 36 is the most active compound in the designed series against EGFR with an IC 50 of 0.1 nM, confirming that pyrrolopyrimidines are attractive drug candidates or lead structures [112]. A late focus on absorption, distribution, metabolism, excretion and toxicology (ADMET) is regarded as one of the main reasons for drug failure [113,114].…”

Section: Cpd 29 Cpd 28mentioning

confidence: 80%

Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

et al. 2018

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Pyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors.

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“…The concept of blocking therapeutic antibodies has also been applied to other upregulated RTKs, such as MET and IGF1R receptors, which have been shown to confer therapeutic resistance and are also excellent targets for combination EGFR therapies (73)(74)(75)(76)(77). Further, therapeutic resistance to HERs antibodies or TKI might involve nonreceptor kinases such as SRC (78) as well as other pathways in a cell-type context-dependent manner. In addition to the potential involvement of HER3, among other mechanisms that are not discussed here, these include inherent or acquired mutations in HERs or signaling components.…”

Section: Blocking Therapeutic Egfr Monoclonal Antibodies From Bench Tmentioning

confidence: 99%

A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy

et al. 2019

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Cancer scientists and clinicians are mourning the death of one of the most accomplished members of their community: Dr. John Mendelsohn. He was a pioneer in targeted cancer therapy and was instrumental for the discovery and deployment of the first antagonist epidermal growth factor receptor (EGFR) therapeutic antibodies, broadening the concept of targeted EGFR therapy to encompass other receptor tyrosine kinases, such as HER2, and developing blocking antibodycombination therapy with chemotherapies or radiotherapy. Dr. Mendelsohn, who died on January 7, 2019, always led by the strength of his accomplishments and the humility of his character. Above all, he was a well-revered mentor and clini-cian, who extended compassion and the gift of his time to patients, colleagues, and mentees alike. In tribute to Dr. Mendelsohn, Cancer Research has invited his former mentees and colleagues who were associated with Dr. Mendelsohn for over three decades to reflect on the broad impact of his work. Here, we discuss Dr. Mendelsohn's illustrious career at three elite academic cancer institutions and hospitals in the United States, his acumen to build, grow, and uplift institutions, and train a generation of medical oncologists, physician scientists, and cancer biologists. His profound legacy on targeted therapy and cancer research and treatment continue to prolong and save the lives of cancer patients globally.

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Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity

Cited by 25 publications

References 53 publications

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy

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