ArticleJournal of computer-aided molecular design2012
Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3).
Article in Journal of computer-aided molecular design, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 42 citations in OpenAlex.
- Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery.Pharmaceutical science advances · 2026Review
- Taurine-Based Hybrid Drugs as Potential Anticancer Therapeutic Agents: In Vitro, In Vivo Evaluations.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Application of Free Energy Perturbation (FEP) Methodology for Predicting the Binding Affinity of Macrocyclic JAK2 Inhibitor Analogues of Pacritinib.ACS medicinal chemistry letters · 2025Article
- Recent advances and future perspectives in small molecule JAK2 inhibitors.Future medicinal chemistry · 2025Review
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT3.Scientific reports · 2023Article
- The odyssey of pacritinib in myelofibrosis.Blood advances · 2022Article
- Novel Treatments for Pediatric Relapsed or Refractory Acute B-Cell Lineage Lymphoblastic Leukemia: Precision Medicine Era.Frontiers in pediatrics · 2022Review
- IRAK1-regulated IFN-γ signaling induces MDSC to facilitate immune evasion in FGFR1-driven hematological malignancies.Molecular cancer · 2021Article
- High MMP-11 expression associated with low CD8+ T cells decreases the survival rate in patients with breast cancer.PloS one · 2021Article
- Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes.Leukemia · 2018Article
- Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy.Oncotarget · 2018Review
- Article
- Emerging treatment options for myelofibrosis: focus on pacritinib.OncoTargets and therapy · 2016Review
- A comprehensive review of pacritinib in myelofibrosis.Future oncology (London, England) · 2015Review
- Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.Biomarker research · 2013Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis.
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