Medicinal Chemistry Approaches Research Articles

Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core

Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC50 values of 1.2 and 0.3 nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays.

Development of bioactive gemcitabine-D-Lys6-GnRH prodrugs with linker-controllable drug release rate and enhanced biopharmaceutical profile

Peptide-drug conjugates have emerged as a potent approach to enhance the targeting and pharmacokinetic profiles of drugs. However, the impact of the linker unit has not been explored/exploited in depth. Gemcitabine (dFdC) is an anticancer agent used against a variety of solid tumours. Despite its potency, gemcitabine suffers mostly due to its unspecific toxicity, lack of targeting and rapid metabolic inactivation. To minimize these limitations and enable its targeting to tumours overexpressing the GnRH receptor, we examined the peptide-drug conjugation approach. Our design hypothesis was driven by the impact that the linker unit could have on the peptide-drug conjugate efficacy. Along these lines, in order to exploit the potential to manipulate the potency of gemcitabine through altering the linker unit we constructed three different novel peptide-drug conjugates assembled of gemcitabine, the tumour-homing peptide D-Lys6-GnRH and modified linker building blocks. Specifically, the linker was sculpted to either allow slow drug release (utilizing carbamate bond) or rapid disassociation (using amide and ester bonds). Notably, the new analogues possessed up to 95.5-fold enhanced binding affinity for the GnRH receptor (GnRH-R) compared to the natural peptide ligand D-Lys6-GnRH. Additionally, their in vitro cytotoxicity was evaluated in four different cancer cell lines. Their cellular uptake, release of gemcitabine and inactivation of gemcitabine to its inactive metabolite (dFdU) was explored in a representative cell line. In vitro stability and the consequent drug release were evaluated in cell culture medium and human plasma. In vivo pharmacokinetic studies were performed in mice, summarizing the relative stability of the three conjugates and the released levels of gemcitabine in comparison with dFdU. These studies suggest that the fine tuning of the linkage within a peptide-drug conjugate affects the drug release rate and its overall pharmaceutical profile. This could eventually emerge as an intriguing medicinal chemistry approach to optimize bio-profiles of prodrugs.

Synthesis and evaluation of α-aminoacyl amides as antitubercular agents effective on drug resistant tuberculosis

The development of an effective antitubercular agent is a challenge due to the complex nature of tuberculosis. Herein, we report the synthesis and evaluation of α-aminoacyl amides as antitubercular agents. The systematic medicinal chemistry approach led to identification of optimal substitutions required for the activity. Compound 11l was identified as antitubercular lead with drug like properties. Further, 11l selectively inhibited M. tuberculosis H37Rv with MIC value of 0.78 μM and was found to be non-toxic to CHOK1 cells. The lead compound inhibited multidrug resistant and Pre-Extensively drug resistant strains of Mycobacterium at 2 μg/mL and 8 μg/mL respectively.

Solubility Enhancement by Various Techniques based on Pharmaceutical and Medicinal Chemistry Approach: An Overview

Solubility Enhancement by Various Techniques based on Pharmaceutical and Medicinal Chemistry Approach: An Overview

Discovery of monoamine oxidase inhibitors by medicinal chemistry approaches.

Neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and depression, have seriously inconvenienced the lives of patients. Growing evidence indicates that these diseases are closely related to the monoamine oxidase (MAO) enzyme, making it an attractive target for the exploitation of potent MAO inhibitors (MAOIs) with high selectivity and low side effects. Although various MAOIs have been discovered, the discovery of an ideal MAOI is not an easy task. In this review, we discuss the currently available rational design strategies for obtaining ideal MAOIs, including ligand-based and receptor-based design strategies, and these strategies were further illustrated with the aid of specific examples from the recent literature. To better understanding the biological activity of MAO, we also highlight the binding modes of typical inhibitors against MAO. Besides, advanced strategies for finding upcoming potent MAOIs were prospected.

Improving vaccines against Streptococcus pneumoniae using synthetic glycans

Streptococcus pneumoniae remains a deadly disease in small children and the elderly even though conjugate and polysaccharide vaccines based on isolated capsular polysaccharides (CPS) are successful. The most common serotypes that cause infection are used in vaccines around the world, but differences in geographic and demographic serotype distribution compromises protection by leading vaccines. The medicinal chemistry approach to glycoconjugate vaccine development has helped to improve the stability and immunogenicity of synthetic vaccine candidates for several serotypes leading to the induction of higher levels of specific protective antibodies. Here, we show that marketed CPS-based glycoconjugate vaccines can be improved by adding synthetic glycoconjugates representing serotypes that are not covered by existing vaccines. Combination (coformulation) of synthetic glycoconjugates with the licensed vaccines Prevnar13 (13-valent) and Synflorix (10-valent) yields improved 15- and 13-valent conjugate vaccines, respectively, in rabbits. A pentavalent semisynthetic glycoconjugate vaccine containing five serotype antigens (sPCV5) elicits antibodies with strong in vitro opsonophagocytic activity. This study illustrates that synthetic oligosaccharides can be used in coformulation with both isolated polysaccharide glycoconjugates to expand protection from existing vaccines and each other to produce precisely defined multivalent conjugated vaccines.

Development of a Novel Class of Agents Targeting the RNA-Splicing Machinery in Myeloid Malignancies

SF3B1 is a splicing factor gene whose mutations are pathognomonic of MDS with ring sideroblasts. Because of the ubiquitous importance of splicing, a major barrier in targeting cells with spliceosomal mutations is the discovery of agents decreasing the competitiveness of mutant cells while preserving the integrity of wild type cells. To date no specific therapies are FDA approved for SF3B1 mutant (SF3B1MT) MDS and few agents are in early clinical testing. We describe a novel targeted approach to drug development for SF3B1MT malignancies.Our investigative strategy started with a high throughput drug screen. We introduced K700E mutation into myeloid cells using CRISPR/Cas9. We then subjected K562+/K700E and matched-parental K562 cells to high throughput drug screen of a library of 3,000 mechanistically annotated, non-redundant, bioactive compounds. Top hits were validated by dose response testing (8 concentrations in half-log dilutions). Our interest focused on compounds with cytostatic activity towards K562+/K700E cells. Among these, a 4-pyridyl-2-anilinothiazole (PAT) showed preferential inhibition of growth in K562+/K700E cells with an IC50 of 3uM. Dose response showed that K562+/K700E cells were significantly sensitive to PAT with a growth inhibition of 20%, 32%, 51%, 65%, 95% at .3uM (P=.01), 1uM (P=.002), 3uM (P<.0001), 10uM (P<.0001), and 20uM (P=.01). High doses (10, 20uM) were toxic to parental cells. PAT treatment did not induce growth arrest in other myeloid cells (THP1, MOLM13FLT3, OCI-AML3DNMT3A, SIG-M5TET2/DNMT3A, K562PHF6) including cells with mutations in other splicing factors (K562U2AF1, K562LUC7L2). PAT induced similar effects in primary SF3B1MT MDS cells at 3uM while it did not induce significant growth inhibition in primary MDS cells with other mutations, including other spliceosomal mutations (e.g.,U2AF1) (N=6). In normal bone marrow cells (N=6), complete growth arrest of erythroid and myeloid cells was observed at high doses (20uM).Using PAT as our lead, we employed a fragment based reiterative medicinal chemistry approach to synthesize selective compounds and improve therapeutic index. Libraries were constructed following Lipinski rules with ease of synthetic construction in mind. Pilot libraries were constructed via the classic Hantsch thiazole synthesis which involves condensation of α-halo ketones with substituted thioureas. This enterprise investigated SAR modifications of PAT by considering features such as regiochemistry and basicity of the nitrogen of the pyridine ring in the head region; replacement of the spacer 2,4-disubstituted thiazole ring with heteroatom containing rings (5,6,7 membered aromatic or aliphatic ring structures); alternatives for the aniline of the tail region e.g., sulfonamide, amide, and substituted amine linkers and substituted aromatic and aliphatic ring structures for the phenyl substituent. A major challenge in drug development of agents targeting spliceosomal mutations is the identification of key clusters of aberrantly spliced genes restored by drug treatment, e.g., identification of a pharmacodynamic endpoint that could be used to prove that that the drug reached its target. SF3B1 mutations induce aberrant 3′-ss selection by promoting use of alternative branch points. To identify biomarkers of splicing changes to screen our libraries, K562+/K700E and parental cells were treated with PAT (3uM) and RNA libraries were subjected to RNA Seq. The splicing pattern of parental cells was used as reference. We identified 328 cassette exons (±25% splicing inclusion difference, pFDR<.05) in K562+/K700E cells of whom the splicing of 22 exons was partially or completely restored upon treatment. Among these, PAT treatment restored the splicing of exons in sensitive 3′-ss sequences (ENOSF1), RNA binding SR-related factors (ACIN1), zing fingers (ZC3H7A) already associated with SF3B1 downregulation, histone modifiers (HMGN3), mitochondrial genes (TMEM126B), proto-oncogenes (CREB1) and heat shock proteins (DNAJC24). Ongoing experiments include tests of the ability of PATs to restore the splicing of misspliced exons and its efficacy in reducing the percentage of SF3B1MT cells in xenografts of K562+/K700E and primary SF3B1MT cells and Sf3b1+/K700E mice.In sum, we described novel classes of compounds that inhibit the expansion of SF3B1MT cells by restoring the splicing defects intrinsically associated with SF3B1. DisclosuresCarraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

Protein engineering by chemical methods: Incorporation of nonnatural amino acids as a tool for studying protein folding, stability, and function

AbstractProteins are large complex biomolecules that act as the effectors of essentially all cell functions. Due to the intrinsic complexity of protein architecture at the microscopic level and the inadequacy of theoretical methods to predict protein reactivity (ie, folding, stability, and function), protein engineering has emerged as a valuable tool to investigate structure–stability–activity relationships in proteins and nowadays recombinant DNA technologies are the “gold standard” for site‐specifically manipulating a given protein chain. The usefulness of current mutagenesis techniques, however, is limited by the relatively poor chemical diversity of the 20 DNA‐coded amino acids, such that it is difficult to precisely assign the observed change of protein stability or function to the variation of a single physicochemical property at a protein site (ie, hydrophobicity, conformational propensity, polarizability, hydrogen bonding, etc). In this article, we report relevant examples from our laboratory showing that chemical methods, that is, enzyme‐catalyzed semisynthesis and stepwise solid‐phase synthesis, allow to conveniently incorporate non‐natural amino acids with “tailored” side chains into small proteins and thus effectively transfer the structure–activity relationship methodology, typical of the medicinal chemistry approach on small molecules, to the study of folding, stability, and molecular recognition in macromolecular protein systems.

A methodology for evaluating multi-objective evolutionary feature selection for classification in the context of virtual screening

Virtual screening (VS) methods have been shown to increase success rates in many drug discovery campaigns, when they complement experimental approaches, such as high-throughput screening methods or classical medicinal chemistry approaches. Nevertheless, predictive capability of VS is not yet optimal, mainly due to limitations in the underlying physical principles describing drug binding phenomena. One approach that can improve VS methods is the aid of machine learning methods. When enough experimental data are available to train such methods, predictive capability can considerably increase. We show in this research work how a multi-objective evolutionary search strategy for feature selection, which can provide with small and accurate decision trees that can be very easily understood by chemists, can drastically increase the applicability and predictive ability of these techniques and therefore aid considerable in the drug discovery problem. With the proposed methodology, we find classification models with accuracy between 0.9934 and 1.00 and area under ROC between 0.96 and 1.00 evaluated in full training sets, and accuracy between 0.9849 and 0.9940 and area under ROC between 0.89 and 0.93 evaluated with tenfold cross-validation over 30 iterations, while substantially reducing the model size.

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.

G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

An OXPHOS Inhibitor Has Antitumor Activity in Multiple Tumor Models

Abstract A medicinal chemistry approach identified IACS-010759 as a clinical-grade small-molecule OXPHOS inhibitor.

Identification of the First Synthetic Allosteric Modulator of the CB2 Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief.

The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands. Here we identify the first ever synthesized positive allosteric modulator (PAM) that targets CB2Rs. The evidence for this was obtained using [3H]CP55940 and [35S]GTPγS binding assays. This finding will be useful for the characterization of allosteric binding site(s) on CB2Rs which will be essential for the further development of CB2R allosteric modulators. Moreover, the new CB2R PAM displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain, raising the possibility that it might be a good candidate for clinical development.

Designing Peptidomimetics.

The concept of a peptidomimetic was coined about forty years ago. Since then, enormous effort and interest have been devoted to mimic the properties of peptides with small molecules or pseudopeptides. The present report aims to review different approaches described in the past to succeed in this goal. Basically, there are two different approaches to design peptidomimetics: a medicinal chemistry approach, where parts of the peptide are successively replaced by non-peptide moieties until getting a non-peptide molecule and a biophysical approach, where a hypothesis of the bioactive form of the peptide is sketched and peptidomimetics are designed based on hanging the appropriate chemical moieties on diverse scaffolds. Although both approaches have been used in the past, the former has been more widely used to design peptidomimetics of secretory peptides, whereas the latter is nowadays getting momentum with the recent interest in designing protein-protein interaction inhibitors. The present report summarizes the relevance of the information gathered from structure-activity studies, together with a short review of the strategies used to design new peptide analogs and surrogates. In the following section, there is a short discussion on the characterization of the bioactive conformation of a peptide, to continue describing the process of designing conformationally constrained analogs producing first and second generation peptidomimetics. Finally, there is a section devoted to reviewing the use of organic scaffolds to design peptidomimetics based on the information available on the bioactive conformation of the peptide.

Abstract 5555: Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers

Abstract Indoleamine-2,3-dioxygenase (IDO1) is well-recognized as an important target for immunotherapeutic intervention. Growing interests on this target have been demonstrated by the recent expansion of enthusiasms to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression for cancer treatment. Clinical validation of IDO1 inhibitors for treating various tumors including glioblastoma, melanoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic diseases are currently pursued by pharmaceutical companies and other sponsors. These IDO1 inhibitors include several pioneering clinical compounds such as INCB024360 (epacadostat), GDC-0919, indoximod, and BMS-986205, etc. At the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO), it was reported that patients with squamous cell carcinoma of head and neck were responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. In addition, epacadostat also demonstrated very promising efficacy in combination with PD-1 checkpoint inhibitors for treating various kind of solid tumors. Most recently, at the 32nd SITC annual meeting held in this month, very exciting and encouraging results were just reported by BMS from an early clinical trials for the combo studies of BMS-986205 with Opdivo. Previously we reported a moderately potent IDO1/TDO dual inhibitor DN131 for cancer immunotherapy (AACR2015 Abstract# 4877), herewith we wish to present a much more potent and selective IDO1 inhibitor DN-016 with superior drug-like properties. DN-016 is a novel heterocyclic compound that was discovered through structure-based drug design and medicinal chemistry approaches. In in vitro studies, DN-016 showed very high potency in inhibiting hela IDO1 cell with an IC50 of 0.71 nM. It exhibited good ADME properties and safe hERG parameter with IC50 over 30 μM. Compared to the reference compounds in clinical stages, DN-016 exhibited much superior permeability with excellent efflux ratio (A-B/B-A: 22 × 10-6 cm.s-1 / 24 × 10-6 cm.s-1). In in vivo rat PK studies, DN-016 showed very high oral bioavailability (100% F) when dosing at 10 mg/kg via po. Currently DN-016 is under preclinical evaluation as a single agent and together with a PD-1 inhibitor. In summary, as a new anticancer agent, DN-016 demonstrated a remarkable in vitro potency and selectivity with favorable pharmacokinetic properties. Detailed preclinical evaluation of DN-016 will be presented. Citation Format: Shoujun Chen, Fengtao Liu, Hongli Guo, Shuwen Ren, Yikun Zeng, Wei Yang, Ping Qing, Tao Chen, Feng Zhou, Guocheng Li, Mingliang Sun, Xiaogang Ye, Xingzhong Zhang, Panhu Zhu, Hui Xu, Pei Li, Donghai Li, Zang Jie, Huanping Li, Shuda Zhao, Jiangjing Tan, Heping Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Jianggang Du, Hongye Yang, Wenting Xue, Pei Wang, Lan Guo, Lu Wang, Qun Li, Yuxun Wang, Daxin Gao. Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5555.

Abstract 2671: 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP

Abstract Using a high throughput gene expression profiling assay directly targeting genes of the androgen receptor pathway, we previously identified the 17beta-hydroxywithanolide (17-BHW), physachenolide C (PCC), as a potent inhibitor of prostate cancer cell growth. Using a panel of prostate cancer cell lines, PCC at low concentrations (IC50 20-50 nM) reduced prostate cancer cell numbers under both standard and 3D in vitro growth conditions. This reduction in cell number was due to growth inhibition and not apoptosis, with PCC causing reductions in the levels of cyclin D, an increase in p21 and arrest of cells in the G1 phase of the cell cycle. Subsequently over 150 natural and semi-synthetic withanolides were evaluated for their ability to inhibit prostate cancer cell growth. All highly active withanolides were 17-BHWs, and some were up to 4-fold more active than PCC. Preliminary structure-activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition, acetoxylation at C-18, an alpha orientation of the side-chain lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as inhibitors of prostate cancer cell growth. Interestingly highly active 17-BHWs rapidly reduced levels of both antiapoptotic cFLIPL and cFLIPS proteins in 22Rv1 prostate cancer cells. However, this reduction did not sensitize 22Rv1 cells to apoptosis. Nonetheless specific reduction of cFLIPL in the castration-resistant 22Rv1 cells using siRNA significantly inhibited their proliferation. This suggests that cFLIPL plays a critical role in the proliferation of some castration-resistant prostate cancer cells. Since the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, this could lead to the identification of highly active natural product-based inhibitors of castration-resistant prostate cancer cell proliferation. The cellular molecular target(s) of active 17-BHWs that promote cFLIP reduction are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E and the University of Arizona. Citation Format: Alan D. Brooks, Nicola E. Wright, Ya-ming Xu, Kithsiri Wijeratne, Poonam Tewary, Neil Cross, A. A. Leslie Gunatilaka, Thomas J. Sayers. 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2671.

Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model

We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches.

DNA topoisomerase II (topo II) is an important enzyme involved in DNA replication, recombination, and repair. Despite the popular applications of topo II inhibitors in cancer therapy, there is still an urgent need to upgrade topo II inhibitors to cope with drug resistance and severe adverse effects. Accordingly, novel topo II catalytic or multitarget topo II inhibitors are gaining more attention and make it possible to ease the toxic limitations of topo II poisons. In this review, medicinal chemistry approaches are mainly discussed toward the development of potent topo II inhibitors with low toxicities.

Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors

Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, with 5% and 10%body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2 dual inhibitor 25a may achieve better clinical benefits.

Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4-b]pyrrolizines as Novel Bruton’s Tyrosine Kinase Inhibitors

An alternative medicinal chemistry approach was conducted on Bruton's tyrosine kinase (BTK) inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4- d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells. Compared to 1, 7S was slightly more selective with strong inhibition on the B-cell receptor signaling pathway. In a TMD8 cell-derived animal xenograft model, 7S showed a relative tumor volume of 5.3 at 15 mg/kg QD dosage that was more efficacious than 1 (RTV 6.6) at a higher dose of 25 mg/kg QD. All these results suggest 7S as a new BTK inhibitor worthy of further profiling.

Recent Synthesis and Discovery of Brefeldin A Analogs.

The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing activity of BFA in cancer cells highlights the possibility of further developing this natural product as an anticancer agent. Besides its biological importance, its structural features have also gathered tremendous interest from both medicinal and synthetic chemists. By a medicinal chemistry and total synthesis approach, numerous analogs from BFA have been developed to improve its inferior bioavailability and its antiproliferative ability. In this review, the recent medicinal chemistry efforts in relation to the production of BFA analogs are extensively presented.