Figure S2: Co-targeting S1P1 and VEGFR2 pathways induced reduction in permeability of retinal vessels. Ter 119 staining (panels A) visualize red blood cells and show that the combination of DC101 and the S1P1 antagonist in the retina led to reduction of the areas of hemorrhage within the vascular plexus and restricted only to the angiogenic front indicating that the remaining vessels in the remodeled area are less permeable.

Figure S3: S1P1 is largely restricted to tumor vessels. Six different tumor models were assessed for S1P1 expression by immunofluorescence. In five of the models S1P1 expression was restricted to tumor vessels. The SK-Hep 1 tumor model was the only model in which some S1P1 expression was also seen on tumor cells in addition to on tumor vessels.

Figure S1: Impedance barrier function assay: The effect of S1P and Ex82 was analyzed using a transendothelial electrical impedance assay. S1P treatment (10 nM) of an endothelial monolayer strongly increases electrical impedance (B) vs control (A) whereas Ex82 has the opposite effect and significantly decreases electrical impedance (D). These results are consistent with the known barrier function of S1P1. In addition, pretreatment with Ex82 blocked the S1P dependent increase in electrical impedance (C).

LY3343544: A novel MET antibody drug conjugate that shows profound pre-clinical in vivo anti-tumor activities, irrespective of MET pathway dependence MET is over-expressed in many types of human tumors. Due to the heterogeneity of human tumors, MET antibodies or small molecule inhibitors have benefited only small subsets of patients with tumors driven by signaling through the c-Met pathway. The patient selection strategies to identify those tumors with MET activation dependence are helpful in predicting sensitivity to many of these inhibitors. It was reported previously that Lilly’s MET antibody, emibetuzumab, showed clinical activity in selective NSCLC patients with high MET IHC staining (90% to 100% 3+ positive) when it was combined with erlotinib in Phase II clinical Trials. In searching for a better treatment for patients carrying the MET overexpression tumors regardless other co-existing mutations, we developed LY3343544, a novel antibody drug conjugate (ADC) molecule that consists of emibetuzumab conjugated with the potent microtubule inhibitor MMAE using a unique lysine conjugation approach. Upon binding to MET, LY3343544 is internalized via receptor-mediated endocytosis. LY3343544 maintains the similar binding and internalization activities to the cell surface MET as compared to emibetuzumab in the competitive cell binding assay and the internalization assay. We reported here that LY3343544 showed profound anti-tumor activity in a preclinical mouse models, and overcome intrinsic resistance mechanisms including KRAS, BRAF, PI3K and TP53 mutations. LY3343544 kills tumor cells expressing a wide range of MET levels on the cell surface and is capable of killing a variety of MET-overexpressing tumor cells including pancreatic, cholanglocarcinoma, colorectal, NSCLC, gastric, head and neck tumor cells in vitro. In contrast, LY3343544 does not kill human normal endothelial cells and normal epithelial cells, no activity on human peripheral blood mononuclear cells with or without activation as well as in cell-based assays. Moreover, LY3343544 is more stable in rodent PK studies than typical inter chain Cys VC-MMAE conjugates and showed tumor regressions in colorectal, NSCLC, gastric and pancreatic mouse xenograft models. Furthermore, LY3343544 shows profound tumor regression in >50% of PDAC PDX models (n=40): 20% complete response (CR); 22.5% partial response (PR); and 17.5% stable disease (SD); overall disease control rate (DCR) is 60%. In addition, LY3343544 shows tumor growth inhibition in cholangiocarcinoma PDX model that is resistant to emibetuzumab. In summary, LY3343544 is highly potent in killing a variety of tumor cells in cell-based killing assays. It demonstrated good stability in vivo and profound anti-tumor efficacy in multiple mouse xenograft models and patient-derived xenograft models thus is a promising agent to treat many types of cancers. Citation Format: Ling Liu, Aaron D. Wrobleski, Yin Yin, Wei Zeng, Xianming Chen, David J. Stokell, Sheng-bin Peng, Amita Datta-Mannan, Gregory P. Donoho, Philip W. Iversen, Philip Hipskind, Yiqing Feng. A novel molecule with profound tumor killing activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 353.

Abstract Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.

Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors.

La presente invention concerne des composes representes par la formule (I), des compositions pharmaceutiques a base de ces composes, et leur utilisation comme antagonistes du recepteur du CRF1 (facteur 1 de liberation de la corticotropine) pour le traitement de troubles psychiatriques et neuroendocriniens, de maladies neurologiques et du syndrome metabolique.

A compound structurally represented by formula I ** (See formula) ** or a pharmaceutically acceptable salt thereof, wherein: Q, T, X and D independently represent carbon or nitrogen, provided that no more than two of Q, T, X and D are nitrogen; R1, R2 and R3 are independently at each occurrence -H, -halogen, (C1-C7), -CN, -C (O) R7, -C (O) (C3-C5), -C ( O) NR7R8, -OCF3, -OR7, -NO2, -NR7R8, -NR9SO2 R7, -NR9C (O) R7, -NR9CO2R7, -NR9C (O) NR7R8, -SR7, -SO2R7, -SO2CF3, -SO2NR7R8, - S (O) R7, -O (CH2) mNR7R8, -heteroaryl-R9, -phenyl-R9, however, with the proviso that when D is nitrogen, then R1 or R2 or R3 are not attached to D, and provided that when X is nitrogen, then R1 or R2 or R3 are not attached to X, and provided that wherein T is nitrogen, then R1 or R2 or R3 are not attached to T, and provided that Q is nitrogen, then R1 or R2 or R3 are not attached to Q; and further provided that when D and X are carbon, then R1 and R2 can be combined to form a 5- or 6-membered D and X ** (See formula) ** wherein the ring so formed you may optionally include one double bond in the case of a five membered ring or two double bonds in the case of a six-membered ring, and wherein one to three ring atoms may optionally be heteroatoms independently selected from N, O or S; wherein m is 1, 2, 3 or 4; R4 and R5 are independently at each occurrence -H, -OH, -halogen, -CF2H, -CF3, (C1-C3), -O- (C1-C3); R6 is independently at each occurrence -H, -halogen, -CF3, (C1-C3), -NH2, -NR7R8, -OH, -OR7; R7 and R8 are independently at each occurrence -H, (C1-C6), wherein R7 and R8 can combine with the atom to which they are attached to form a ring of 3 to 7 members; R9 is independently at each occurrence -H, (C1-C3); with the proviso that the compound is other than [4- (6-amino-5-hydroxy-pyridin-3-yl) -phenyl] - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone.

Cyclopentaneinheiten in Naturstoffen wie (–)‐Sterepolid 3 sind nicht leicht zu synthetisieren. Ein neuer Weg get vom nicht‐terminalen Alkin 1 aus. Seine Cycloisomerisierung zu 2 gelingt in Gegenwart von Palladium(II)‐acetat und dem Liganden N,N′ ‐Bis(benzyliden)ethylendiamin. Dieses Katalysatorsystem cyclisiert auch andere Enine vom Typ 1 mit z. B. CH 2 OCH 3 oder CH 3 anstelle von OSiMe 2 t Bu – was Pd(OAc) 2 allein nicht schafft (R = p ‐H 3 COC 6 H 4 CH 2 ). magnified image