Design and synthesis of boron-containing ALK inhibitor with favorable in vivo efficacy.

ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALKL1196M IC50 = 8.4 nM, NCI-H2228 cells IC50 = 520 nM) and better in vitro metabolic stability (human liver microsomes, T1/2 = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor.

Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors.

Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are very promising targets for hematological malignancies and autoimmune diseases. In recent years, a few compounds have been approved as a marketed medicine, and several are undergoing clinical trials. By recombining the dominant backbone of known active compounds, constructing a foused library, and screening a broad panel of kinases, we found a class of compounds with dual activities of anti-BTK and anti-JAK3. Some of the compounds have shown 10-folds more active in the enzyme and cell-based assays than a known active compound. Furthermore, liver microsome stability experiments show that these compounds have better stability than ibrutinib. These explorations offered new clues to discover benzoxaborole fragment and pyrimidine scaffold as more effective BTK and JAK3 dual inhibitors.

Primary central carcinoma ex pleomorphic adenoma of the mandible: report of a rare case and literature review.

We report a rare case of primary carcinoma ex pleomorphic adenoma (CXPA) of the mandible. A 13-year-old girl presented with a large mass, measuring about 30 cm in its greatest dimension, involving the mandible. She was referred to our department for surgery, and her postoperative course was uneventful; she is currently free from the disease 48 months after surgery. Primary CXPAs located centrally within the jawbones are rare with only 10 cases reported in the English and Chinese literature. This case illustrates 2 key facts regarding the diagnosis and therapy of CXPA. First, clinicians should be aware of this possibility and should emphasize the need for submission of so-called cystic lytic lesions for histopathologic analysis. Second, tumors should be excised en bloc with adjuvant postoperative radiotherapy when local recurrence and regional metastasis are suspected clinically.

[Tumors of different histological type in unilateral salivary glands: a case report].

Tumors of synchronous benign and malignant in unilateral salivary glands have rarely been reported. A case of 21-year-old girl who was diagnosed as synchronously adenoid cystic carcinoma of the left parotid and pleomorphic adenoma of the left submandibular gland. The classification, clinic pathology, diagnosis, possible mechanism were discussed based on similar literatures.