Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT0006012

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Pharmacophore modeling and 3D QSAR analysis of isothiazolidinedione derivatives as PTP1B inhibitors

The article describes the development of a robust pharmacophore model and investigation of structure activity relationship analysis of 56 isothiazolidinedione derivatives reported as PTP1B inhibitors. A six-point pharmacophore model consisting of four aromatic rings (R), one hydrogen bond donor (D) and one hydrogen bond acceptor (A) with discrete geometries as pharmacophoric features was developed and the generated pharmacophore model was used to derive a predictive 3D QSAR model for the studied dataset. The obtained 3D QSAR model has an excellent correlation coefficient value (r = 0.98) along with good statistical significance as shown by a high Fisher ratio (F = 428.60). The model also exhibits good predictive power confirmed by the high value of cross-validated correlation coefficient (q = 0.62). The QSAR model suggests that hydrophobic aromatic character is crucial for the PTP1B inhibitory activity at the R-15 site

Tuning Activity of Antimicrobial Peptides by Lipidation

Antimicrobial peptides (AMPs) are amino acid-based bioactive molecules that specifically target microbes. As such, they are a potent class of antibiotics, especially against bacterial infections. Naturally occurring AMPs are usually too long to be considered for therapeutic applications. To solve this, short sequences that mimic the activity of AMPs are designed. However, such endeavors are often accompanied with a reduction in antibacterial activity. To counter this, lipophilic molecules can be attached that function as a lipid anchor and target the short sequence to the bacterial membrane. For a range of short AMPs, this strategy has proven to lead to more active constructs. Although these lipidated short AMPs often work as complex target specific surfactants, more delicate modes of action that do not deviate too much from the nonlipidated counterparts are also known. This is readily observed by the large differences in activities that are detected when alterations in the lipid chain length and chirality of the amino acids residues are implemented. It is not uncommon to see that inactive or poorly active short AMPs can be turned into potent antibacterial agents. Importantly, selectivity of the short lipidated AMPs (lipoAMPs) for the bacterial membrane can be enhanced by alteration of the amino acid chirality. This strategy has led to lipoAMPs with submicromolar activities; in fact, activities that rival that of vancomycin have been observed for several short AMPs. Future research needs to determine (i) the effect of lipidation on the formation of lipid rafts in the bacterial membrane, (ii) if structural complications like branched lipids or chiral substituents on the lipid chain can be used to further increase the activity and selectivity of the conjugates, and (iii) if additional functionalities other than a membrane-anchoring ability can be bestowed on the lipid chain, e.g., redox activity or scavenger for small molecular components that traverse the lipid membrane. The interplay between degree of lipophilicity and the chirality of the amino acids of the AMP also needs further exploration, especially to see if more potent and selective (lipo)AMPs can be obtained that can be applied systemically. It may also be advisable to measure the most potent lipoAMPs in a centralized facility in order to obtain objective and comparable antibacterial activities

Molecular modeling and synthesis of ZINC02765569 derivatives as protein tyrosine phosphatase 1B inhibitors: lead optimization study

This article describes design, synthesis, and molecular modeling studies of the ZINC02765569 derivatives as potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, which was previously reported as a vHTS hit (ZINC02765569) by our laboratory. Ten compounds were synthesized and characterized by IR, MASS, and NMR followed by in vitro screening for PTP1B inhibition and glucose uptake in skeletal muscle L6 myotubes. The most potent compound 3j shows 66.4 % in vitro PTP1B inhibition and 39.6 % increase in glucose uptake. Glide was used to study the nature of interactions governing binding of designed molecules with active site of the PTP1B enzyme