knockout

SW033291 是有效的15-PGDH 抑制剂，与15-PGDH 亲和力高，Ki 为 0.1 nM。它增加骨髓和其他组织中前列腺素 PGE2 的水平。它还可促进组织再生。

MK-1064 (Urokinase inhibitor 1) 是一种选择性食欲素 2 (2-SORA)受体拮抗剂，可用于失眠患者的研究。

iFSP1 是一种强效、选择性和谷胱甘肽独立的铁死亡抑制蛋白 1 (FSP1) (AIFM2) 抑制剂，具有EC50 为 103 nM。它能够使多种人类癌细胞系对铁死亡诱导剂敏感，例如 (1S,3R)-RSL3。它在过表达 FSP1 的 GPX4 敲除细胞中选择性地诱导铁死亡。

Tamoxifen 是一种口服有效的选择性雌激素受体调节剂（SERM），对雌激素在乳腺细胞中具有拮抗作用，在骨、肝和子宫细胞中具有激动作用，可用于诱导基因敲除、小鼠肝损伤模型，同时具备激活Hsp90、诱导自噬与凋亡、抑制EBOV和MARV病毒感染等多种生物学活性。

Tamoxifen Citrate 是一种口服有效的选择性雌激素受体调节剂（SERM），可阻断乳腺细胞中的雌激素作用，同时激活骨骼、肝脏和子宫等细胞中的雌激素活性，作为Hsp90激活剂可增强其分子伴侣ATPase活性，能激活自噬、诱导凋亡，并可用于构建CreER(T2)转基因小鼠的基因敲除及肝损伤模型。

24-Norursodeoxycholic acid (nor-UDCA) 是一种侧链缩短的 UDCA 的 C23 同系物，表现出有效的抗胆汁淤积，抗炎和抗纤维化活性。

PRDX1-IN-3（SOMCL-19-048）是一种具有抗结直肠癌活性的PRDX1共价抑制剂。PRDX1-IN-3能有效抑制结直肠癌细胞的增殖，并显著降低对携带PRDX1基因敲除的结直肠癌裸鼠的抗肿瘤作用。PRDX1-IN-3还能上调p53信号通路下游基因，发挥抗癌作用。

LH1513 是 l-lysine 的二草酸 (dioxalate) 盐衍生物，能够抑制CaOx结晶，其效果优于柠檬酸盐和丙酮酸盐。在高草酸尿症模型中，LH1513 展示了预防活性的潜力，并且在 Agxt 敲除小鼠中能有效防止尿液中 CaOx 晶体形成。AGXT-1 是一种在线粒体中运作的蛋白质，参与代谢过程。

TFE-IDAtp1-LinA 是 Stp 含三氟乙基亚氨基二乙酸类似物的有效两亲载体。它与 Cas9 RNP ssDNA 结合形成纳米颗粒，可有效实现增强型绿色荧光蛋白的敲除，ED50 为 0.38 nM 的 Cas9 sgRNA 核糖核蛋白 (RNP)。

FMP-API-1 是一种 A-kinase anchoring protein (AKAP)-PKA 相互作用的抑制剂。它与 PKAR 亚基的变构位点结合，并在肾皮质集合管 (mpkCCD 细胞) PKA 敲除细胞系中提升 PKA 和 AQP2 的活性。FMP-API-1 对于肾源性尿崩症 (NDI) 的研究具有潜在意义。

Hypoxystat 可提高血红蛋白对氧气的亲和力，减少氧气在组织中的释放，诱导组织缺氧。在 Ndufs4 基因敲除小鼠模型中，Hypoxystat 可缓解线粒体疾病 Leigh 综合征，并且具有口服活性。

TDI-012804 是一种 TNKS2 抑制剂，选择性抑制细胞内源性 TNKS2 蛋白。该化合物增加了 TNKS1 杂合子 (Tnks1HET) 和完全敲除 (Tnks1KO) 细胞中 AXIN1 蛋白的表达。TDI-012804 能够抑制 ApcQ1405X/Tnks1KO 类器官的增殖，EC50 为 59.1 nM，并表现出对 Tnks1KO AKP-G12D 和 AKP-G13D 类器官的选择性毒性。

LY-465608, a PPAR Agonist, inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice.

Potent and selective p38α and p38β degrader (DC50 < 50 nM). Displays no significant degradation of p38γ, p38δ, JNK1/2 or ERK1/2. Inhibits phosphorylation of MK2 in UV-treated cancer cells and LPS-stimulated bone marrow-derived macrophages (BMDM). Exhibits similar effect to p38α gene knockout in BBL358 cells. Active in vivo.

GLP-1 amide is a peptide hormone cleaved from proglucagon in the pancreas.1,2 Mice lacking the glucagon receptor (Gcgr- -) have approximately nine-fold higher levels of total GLP-1 amide, including GLP-1 (1-36) amide and truncated GLP-1 (7-36) amide , in pancreatic tissue compared to wild-type mice.2References1. Schjoldager, B.T., Mortensen, P.E., Christiansen, J., et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig. Dis. Sci. 34(5), 703-708 (1989).2. Gelling, R.W., Du, X.Q., Dichmann, D.S., et al. Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 100(3), 1438-1443 (2003). GLP-1 amide is a peptide hormone cleaved from proglucagon in the pancreas.1,2 Mice lacking the glucagon receptor (Gcgr- -) have approximately nine-fold higher levels of total GLP-1 amide, including GLP-1 (1-36) amide and truncated GLP-1 (7-36) amide , in pancreatic tissue compared to wild-type mice.2 References1. Schjoldager, B.T., Mortensen, P.E., Christiansen, J., et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig. Dis. Sci. 34(5), 703-708 (1989).2. Gelling, R.W., Du, X.Q., Dichmann, D.S., et al. Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 100(3), 1438-1443 (2003).

CAY10748 is an agonist of stimulator of interferon genes (STING; IC50= 0.3794 μM in a competition binding assay).1It activates STING in STING-expressing, but not STING knockout, THP-1 cells (EC50s = 0.287 and >100 μM, respectively, in a reporter assay). It induces phosphorylation of STING at the serine in position 366, as well as phosphorylation of TBK1 and IFN regulatory factor 3 (IRF3), indicating activation of the STING-TBK1-IRF3 signaling pathway. CAY10748 increases the secretion of IFN-β and the levels of chemokine (C-X-C motif) ligand 10 (CXCL10), and IL-6 in peripheral blood mononuclear cells (PBMCs) when used at a concentration of 10 μM. It also reduces tumor growth in a CT26 murine colon cancer model when administered at a dose of 0.15, but not 1.5, mg/kg. 1.Xi, Q., Wang, M., Jia, W., et al.Design, synthesis, and biological evaluation of amidobenzimidazole derivatives as stimulator of interferon genes (STING) receptor agonistsJ. Med. Chem.63(1)260-282(2019)

Deltorphin II is a peptide agonist of δ2-opioid receptors.1,2It is selective for δ-opioid receptors over μ- and κ-opioid receptors in radioligand bindings assays (Kis = 0.0033, >1, and >1 μM, respectively) and induces [35S]GTPγS binding in mouse brain membrane preparations (EC50= 0.034 μM). Deltorphin II (0.12 mg kg) decreases the infarction zone:risk zone ratio in a rat model of myocardial ischemia-reperfusion injury induced by coronary occlusion, an effect that can be reversed by the δ2-opioid receptor antagonist naltriben but not the δ1-opioid receptor antagonist BNTX.3Intrathecal administration of deltorphin II (15 μg animal) increases latency to withdraw in the paw pressure and tail-flick tests in rats.4 1.Raynor, K., Kong, H., Chen, Y., et al.Pharmacological characterization of the cloned κ-, δ-, and μ-opioid receptorsMol. Pharm.45(2)330-334(1994) 2.Scherrer, G., Befort, K., Contet, C., et al.The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: A parallel study of mu, delta and combinatorial opioid receptor knockout miceEur. J. Neurosci.19(8)2239-2248(2004) 3.Maslov, L.N., Barzakh, E.I., Krylatov, A.V., et al.Opioid peptide deltorphin II simulates the cardioprotective effect of ischemic preconditioning: role of δ2-opioid receptors, protein kinase C, and KATP channelsBull. Exp. Biol. Med.149(5)591-593(2010) 4.Labuz, D., Toth, G., Machelska, H., et al.Antinociceptive effects of isoleucine derivatives of deltorphin I and deltorphin II in rat spinal cord: A search for selectivity of delta receptor subtypesNeuropeptides32(6)511-517(1998)

Dynamin-related GTPase DRP1 partial inhibitor (IC50 = 1.2 μM). Selective for DRP1 over other dynamin-related GTPases, OPA1 and DYN1. Increases mitochondrial DNA levels in mfn1- knockout MEFs deficient in mitochondrial fusion. Mallat et al (2018) Discovery and characterization of selective small molecule inhibitors of the mammalian mitochondrial division dynamin, DRP1. Biochem.Biophys.Res.Commun. 499 556 PMID:29601815

Potent and selective orexin OX2 receptor agonist (EC50 = 28 nM at human OX2 expressed in CHO cells). Displays approximately 100-fold selectivity for OX2 over OX1 (EC50 = 2.75 μM at human OX1 expressed in CHO cells). Depolarizes OX2-expressing histaminergic neurons in mouse brain slices. Increases wake time in wild type mice. Suppresses cataplexy-like symptoms in OX knockout mice. Nagahara et al (2015) Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J.Med.Chem. 58 7931 PMID:26267383 |Irukayama-Tomobe et al (2017) Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc.Natl.Acad.Sci.USA. 144 5731 PMID:28507129

1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PE is a phospholipid that contains stearic acid at the sn-1 position and 15(S)-HpETE at the sn-2 position. It is produced via oxidation of 1-stearoyl-2-arachidonoyl-sn-glycero-3-PE by 15-lipoxygenase (15-LO). 1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PE (0.6 and 0.9 μM) increases ferroptotic cell death in wild-type and Acsl4 knockout Pfa1 mouse embryonic fibroblasts (MEFs) treated with the GPX4 inhibitor RSL3.

Produced by neutrophils, macrophages, mast cells, and by transcellular metabolism in platelets, leukotriene C4 (LTC4) is the parent cysteinyl leukotriene formed by the LTC4 synthase-catalyzed conjugation of glutathione to LTA4. It is one of the constituents of slow-reacting substance of anaphylaxis (SRS-A) and exhibits potent smooth muscle contracting activity. LTC4, however, is rapidly metabolized to LTD4 and LTE4, which makes the characterization of LTC4 pharmacology difficult. N-methyl Leukotriene C4 (N-methyl LTC4) is a synthetic analog of LTC4 that is not readily metabolized to LTD4 and LTE4.It acts as a potent and selective CysLT2 receptor agonist exhibiting EC50 values of 122 and > 2,000 nM at the human CysLT2 and CysLT1 receptors, respectively. It has essentially the same potency as LTC4 at both the human and murine receptors CysLT2 receptors. N-methyl LTC4 is potent and active in vivo, causing vascular leak in mice overexpressing the human CysLT2 receptor but not in CysLT2 receptor knockout mice.

STING agonist 1a is an agonist of stimulator of interferon genes (STING).1It induces expression of an IRF-inducible SEAP reporter gene in a cell-based assay (EC50= 16.77 μM). STING agonist 1a (12.5-100 μM) induces expression of IFN-β, IL-6, and chemokine (C-X-C motif) ligand 10 (CXCL10) in THP-1 cells, an effect that can be reversed by STING knockout or the STING inhibitor H-151 . 1.Hou, H., Yang, R., Liu, X., et al.Discovery of triazoloquinoxaline as novel STING agonists via structure-based virtual screeningBioorg. Chem.100103958(2020)

Potent trace amine 1 (TA1) receptor agonist (EC50 values are 0.12, 35 and 17-85 nM for mouse, rat and human receptors, respectively). Increases wakefulness and reduces REM and NREM sleep duration in wild type mice. Inhibits spontaneous locomotor activity in dopamine transport (DAT) knockout mice. Espinoza et al (2018) Biochemical and functional characterization of the trace amine-associated receptor 1 (TAAR1) agonist RO5263397. Front.Pharmacol. 9 645 PMID:29977204 |Galley et al (2015) Discovery and characterization of 2-aminooxazolines as highly potent, selective, and orally active TAAR1 agonists. ACS.Med.Chem.Letts. 7 192 PMID:26985297 |Schwartz et al (2017) Trace amine-associated receptor 1 regulates wakefulness and EEG spectral composition. Neuropsychopharmacology. 42 1305 PMID:27658486

JHU-58 is a novel dipeptide MrgC agonist. JHU-58 inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury.