BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy.

Zinc(II)-dipicolylamine (Zn-DPA) has been shown to specifically identify and bind to phosphatidylserine (PS), which exists in bulk in the tumor microenvironment. BPRDP056, a Zn-DPA-SN38 conjugate was designed to provide PS-targeted drug delivery of a cytotoxic SN38 to the tumor microenvironment, thereby allowing a lower dosage of SN38 that induces apoptosis in cancer cells. Micro-Western assay showed that BPRDP056 exhibited apoptotic signal levels similar to those of CPT-11 in the treated tumors growing in mice. Pharmacokinetic study showed that BPRDP056 has excellent systemic stability in circulation in mice and rats. BPRDP056 is accumulated in tumors and thus increases the cytotoxic effects of SN38. The in vivo antitumor activities of BPRDP056 have been shown to be significant in subcutaneous pancreas, prostate, colon, liver, breast, and glioblastoma tumors, included an orthotopic pancreatic tumor, in mice. BPRDP056 shrunk tumors at a lower (~20% only) dosing intensity of SN38 compared to that of SN38 conjugated in CPT-11 in all tumor models tested. A wide spectrum of antitumor activities is expected to treat all cancer types of PS-rich tumor microenvironments. BPRDP056 is a first-in-class small molecule drug conjugate for cancer therapy.

Design and synthesis of novel 3-sulfonylpyrazol-4-amino pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.

Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate.

Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.

A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model.

Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray.

PURPOSE: The incidence and mortality rates of cervical cancer are declining in the United States; however, worldwide, cervical cancer is still one of the leading causes of death in women, second only to breast cancer. This disparity is at least partially explained by the absence of or comparatively ineffective screening programs in the developing world. Recent advances in expression genomics have enabled the use of DNA microarray to profile gene expression of various cancers. These expression profiles may be suitable for molecular classification and prediction of disease outcome and treatment response. We envision that expression genomics applied in cervical cancer may provide a more rational approach to the classification and treatment of the disease. EXPERIMENTAL DESIGN: In this report, we examined the expression profiles of cervical cancer compared with normal cervical tissues in DNA microarrays that contained approximately 11,000 features that correspond to either human transcripts with known function or anonymous expressed sequence tags. RESULTS: Our results showed that normal cervical tissues were completely segregated from the cancer samples using about 40 genes whose expressions were significantly different between these specimens. In addition, clinical stage IB and stage IIB tumors could also be classified based on their signature expression patterns. Most importantly, some of the tumor samples were further stratified into two major groups based on their response to radiotherapy, and we were able to predict the response of these patients to radiotherapy from their expression profiles. CONCLUSIONS: Gene expression profiling by DNA microarray may be used for further molecular classification of disease stages and prediction of treatment response in cervical cancer.

Gemcitabine combined with sequential paclitaxel and carboplatin in patients with urothelial cancers and other advanced malignancies.

BACKGROUND: To investigate a novel schedule of gemcitabine (G), paclitaxel (P), and carboplatin (C), based on preclinical studies demonstrating greater activity and decreased toxicity of administering P prior to C. MATERIAL/METHODS: The effect of the P and C drug sequence on tumor cell viability was assessed with a tetrazolium assay on T24 bladder and DU145 prostate cancer cells. Patients with transitional cell cancer (TCC) and other advanced malignancies were treated with G and P on days 1, 8, and 15 of each 28 day cycle. C was administered on day 2 at an AUC of 5. Doses of G and P were varied among cohorts of three patients. RESULTS: Preclinical studies demonstrated that the sequence of P followed by C induced greater cytotoxicity than the reverse sequence. The recommended phase II dose (RPTD) was defined as 70 mg/m2 P, 300 mg/m2 G, and C with AUC of 5. Therapy was well tolerated; fever and neutropenia occurred in only one patient at the RPTD. Grade 3 thrombocytopenia occurred in 5 of 21 patients treated at the RPTD. Out of all 37 patients treated on study, 9 achieved a partial tumor response (PR) and two patients achieved a complete response (CR). Out of the 15 patients with TCC, six had a PR and two had a CR. CONCLUSIONS: Preclinical studies demonstrated that the sequence of paclitaxel followed by carboplatin was more effective than the opposite sequence. Administration of gemcitabine and paclitaxel followed by carboplatin was well tolerated and clinically active. GCP should be compared to other combination regimens under investigation for the treatment of TCC.