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We aimed to uncover genetic factors affecting resistance to the cancer drug olaparib. To do this, we utilized multiomics matrix factorization (MOFA), a multiomics approach, to explore omic-based features that might become biomarker candidates. Our results showed that 17 damaging mutations, 6 gene expression signatures, 17 DNA methylations, and 26 transcription-factor activities can impact the refractory response to olaparib.To verify the potential utility of the identified biomarker candidates, we generated a predictive model to differentiate between olaparib responding and nonresponding cell lines using machine learning techniques, including support vector machine algorithms, random forest algorithms, and Siamese neural networks. The model was centered around six gene-expression biomarker candidates and validated using the Genomics of Drug Sensitivity in Cancer database.Our findings suggest that using a multiomics approach with machine learning methods can lead to a better understanding of the mechanism of drug resistance and identify biomarkers, which will ultimately facilitate the appropriate administration of drugs to patients. The source codes can be found athttps://github.com/wjlim/DrugResistance.

[Image: see text] HIV persistence in latently infected, resting CD4(+) T cells is broadly considered a barrier to eradicate HIV. Activation of the provirus using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs has been touted as a promising therapeutic approach. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. Several clinical HDAC inhibitors had been examined as LRAs, which induced HIV activation in vitro and in vivo. Here we report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells. The SAR led to the discovery of a highly selective class I HDAC inhibitor 10 with excellent potency. HDACi 10 induces the HIV gag P24 protein in patient latent CD4(+) T cells.

The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.

Novel analogs of (-)-saframycin A are described. The analogs are shown to be potent inhibitors of the in vitro growth of several tumor cells in a broad panel and promising as leads for further optimization. The first in vivo studies in a solid tumor model (HCT-116) reveal potent antitumor activity with associated toxicity of daily administration.

Human trials on the globo H carbohydrate vaccine (see picture, KLH=the carrier protein keyhole limpet hemocyanin) show that it produces strong IgM, and in some cases IgG, responses in patients with progressive and recurrent prostate cancer. Furthermore, these antibodies not only recognize synthetic antigens, but also globo H-positive tumors in biopsy extracts and tumor tissues.

A concise and potentially practical synthesis of the title compound has been achieved. The route features a high degree of convergence and economy of synthetic operations. A key step is the concurrent introductory addition of three α-l-fucosyl residues at required hydroxyl acceptor sites (see 37 → 39). Conjugation to carrier protein was achieved, and a route to include truncated structures for investigations for antibody specificity was accomplished.

A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.

A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (CaV3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.

There is mounting evidence to suggest that immunization-based strategies can be used to mobilize the human immune system against specific carbohydrate antigens displayed on the surface of cancer cells. Following isolation and identification, such antigens can be administered as conjugate vaccines. The tumor-associated carbohydrate antigen KH-1 is 1 such antigen and may serve as a potential target for immunization against adenocarcinoma. However, a serious impediment to the application of a vaccine-based approach involving this antigen is that its availability from natural sources is severely limited. In order to overcome this limitation, we have developed an efficient total synthesis of this complex glycolipid. We have extended our synthesis to reach a structurally related analog in which the ceramide portion of KH-1 is replaced with an allyl substituent. These synthetic advances have led to the preparation of 2 potential vaccine constructs, each based on the conjugation of the KH-1 nonasaccharide and the carrier protein keyhole limpet hemocyanin (KLH). In 1 construct (KH-1-Et-KLH), the nonasaccharide is conjugated to KLH via a simple ethyl linkage, while in the other (KH-1-MMCCH-KLH), conjugation is mediated by a 4-(4-N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide (MMCCH) cross-linker. We report here the immunological properties of these 2 constructs. Mice were immunized with either of the 2 KH-1-KLH vaccine candidates or the KH-1 ceramide, along with the immunological adjuvant QS-21. Immunization with the ceramide served as a negative control and, as expected, failed to stimulate the production of antibodies against the KH-1 glycolipid. The construct in which the KH-1 nonasaccharide is linked to KLH via a simple alkyl chain stimulated significant quantities of IgM antibodies, whereas the construct linked to KLH by MMCCH induced high titers of both IgM and IgG antibodies. Inhibition data demonstrated that antibodies generated in response to immunization with the KH-1-KLH constructs recognize not only the KH-1 antigen but also the Lewisy (Ley) antigen, which, from a structural perspective, is similar to the 4 residues located at the non-reducing end of the KH-1 nonasaccharide. Thus, the KH-1-KLH constructs elicit an immune response that successfully targets 2 adenocarcinoma markers. As assessed by FACS analysis, the antibodies raised were strongly reactive with the KH-1/Ley positive cell line MCF-7 but not with KH-1 and Ley negative melanoma cell lines. Based on the results of our study, a KH-1-KLH plus QS-21 vaccine is being prepared for clinical evaluation. © 2002 Wiley-Liss, Inc.

The total syntheses of two octasaccharide antigens isolated from human milk, 1 and 2, and their corresponding allyl glycosides, 3 and 4, have been achieved by utilizing the glycal method. Convergent assembly of the core hexasaccharides and concurrent introduction of two α-l-fucosyl moieties at the late stage of the syntheses provided these complex carbohydrates in a concise manner. With synthetic material obtained, biological evaluations of these antigens as potential gastrointestinal cancer immunotherapeutic agents have been initiated.

The total syntheses of two octasaccharide antigens isolated from human milk, 1 and 2, and their corresponding allyl glycosides, 3 and 4, have been achieved by utilizing the glycal method. Convergent assembly of the core hexasaccharides and concurrent introduction of two alpha-L-fucosyl moieties at the late stage of the syntheses provided these complex carbohydrates in a concise manner. With synthetic material obtained, biological evaluations of these antigens as potential gastrointestinal cancer immunotherapeutic agents have been initiated.

Immunological study of Globo-H, a breast tumor associated carbohydrate antigen, has been producing promising results. As the demand for the supply of this antigen grows, the efficient production of enough material has become an urgent problem. We have been trying to solve this problem by two approaches: the solid support synthesis of Globo-H, and the development of efficient conjugation methods. For the solid support synthesis, solution phase direct roll-over reactions have been performed to verify the possibility that this method can be used to install the 2-amino-2-deoxy galactose moiety on the polymer support. From the results of these reactions, a tumor associated nonasaccharide antigen KM-i has been synthesized. To improve the conjugation yield of Globo-H to a carrier protein KLH (keyhole lympet hemocyanin), a model study has been carried out to implement an N-hydroxy succinimide ester conjugation method. At the same time, sufficient amounts of Globo-H have been synthesized by solution phase protocol for further immunocharacterization.

Human trials on the globo H carbohydrate vaccine (see picture, KLH=the carrier protein keyhole limpet hemocyanin) show that it produces strong IgM, and in some cases IgG, responses in patients with progressive and recurrent prostate cancer. Furthermore, these antibodies not only recognize synthetic antigens, but also globo H-positive tumors in biopsy extracts and tumor tissues.

Many human carcinomas overexpress the Lewis(y) (Le[y]) blood-group epitope [Fucalpha1-->2Galbeta1-->4 (Fucalpha1-->3)GlcNAcbeta1-->3Gal-]. With a view to developing Le(y) based vaccines we have examined the immunogenicity of Le(y)-protein conjugates in mice. Le(y) pentasaccharide was synthesized as its allyl glycoside and coupled to keyhole limpet hemocyanin (KLH) by reductive amination or by a novel method utilizing a maleido-derivitized alkyl carboxyhydrazide as a bridging group to 2-iminothiolane-derivitized KLH. Le(y) oligosaccharide was also coupled to bovine serum albumin by reductive amination. Immunization of groups of mice with the three conjugates, together with the immunological adjuvant QS21, showed that Le(y) oligosaccharide directly coupled to KLH was the most efficient conjugate for eliciting IgG and IgM antibody responses to naturally occurring forms of Le(y) epitopes carried on mucins and glycolipids. These antibodies were also reactive with and cytotoxic to a human breast cancer cell line expressing Le(y) (MCF-7). These experiments suggest that Le(y)-KLH antigen and QS21 adjuvant could be considered as an immunogenic therapeutic vaccine in carcinoma patients.