Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent.

Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors.

Acute myeloid leukemia (AML) is an aggressive cancer, which is characterized by clonal expansion of myeloid progenitors in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) mutations are the most frequently identified mutations, present in approximately 25-30 % AML patients, making FLT3 inhibitors a crucial treatment option for AML. In this study, we described the design, synthesis and biological evaluation of a series of 2-aminopyrimidine derivatives as potent FLT3 inhibitors.

Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities.

FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor , which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations.

Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia.

FLT3 inhibitors (FLT3i) are widely used for the treatment of acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells.

Discovery of new macrophage M2 polarization modulators as multiple sclerosis treatment agents that enable the inflammation microenvironment remodeling.

The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities.

Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells.

Multiple myeloma (MM) is a highly malignant hematologic cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC = 24 nM in MM.

Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT.

Herein, we report two promising compounds and possessing nanomolar FLT3 inhibitory activities (IC = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC = 0.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent.

Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies.

Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC of 0.