small molecule inhibitors

DS-003是一种小分子Gp120抑制剂。作为BMS-378806的类似物，DS003在较长暴露时间及与融合抑制剂联合使用时显示出增强的抑制活性。然而，可溶性CD4+的预先暴露会阻碍DS003与病毒包膜的结合。研究表明，由于DS003针对Gp120的CD4+结合位点，它是预防暴露前预防治疗的有前途的候选化合物。

Zotiraciclib（又名TG02和SB1317）是一种新型小分子化合物，具有强效的CDK JAK2 FLT3抑制作用。该化合物可通过抑制周期蛋白依赖性激酶9（CDK9），耗竭Myc来治疗能穿越血脑屏障的癌症。Zotiraciclib是正在研究的众多CDK抑制剂之一，其他针对CDK9的化合物，用于治疗急性髓细胞性白血病的还包括alvocidib和atuveciclib。许多癌症中的Myc过表达是一个已知因素，其中80%的胶质母细胞性瘤展现此特性。

5,6-dihydroxy-1,3-dihydro-2-benzofuran-1-one(5,6-二羟基异苯并呋喃-1(3H)-酮)是一种邻苯二甲酸酐，可用于有机合成和生化实验，在专利WO2010053606中用于合成使蛋白质合成失活的小分子抑制剂。

7,8-Dihydroxy-4H-chromen-4-one 是一个活性小分子，常用作分子砌块来合成 E3 泛素蛋白连接酶抑制剂。

PF-06807656 is insensitive to the introduction of the N171D mutation in the ROMK conduction pore that greatly diminishes the activity of other small-molecule inhibitors. PF-06807656 is an effective ROMK inhibitor (Tl+ flux IC50 = 160 nM).

CBIP is a small-molecule inhibitors of botulinum neurotoxin serotype A light chain (BoNT/A LC). CBIP possesses low micromolar activity against BoNT/A.

Insulin-degrading enzyme (IDE) is a thiol-sensitive zinc-metallopeptidase that acts as the major insulin-degrading protease in vivo, mediating the termination of insulin signaling. [1] In addition to regulating insulin action in diabetes pathogenesis, IDE plays a role in Varicella-Zoster virus infection and degradation of amyloid-β, a peptide implicated in Alzheimer's disease. ML-345 is a small molecule inhibitor that selectively targets cysteine819 in IDE with an EC50 value of 188 nM. [2] It demonstrates 10-fold selectivity for IDE over a panel of enzymes with reactive cysteine residues.[2] Reference：[1]. Maianti, J.P., McFedries, A., Foda, Z.H., et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511(7507), 94-98 (2014).[2]. Bannister, T.D., Wang, H., Abdul-Hay, S.O., et al. ML345, a small-molecule inhibitor of the insulin-degrading enzyme (IDE). 1 R03 DA024888-01 (MLSCN cycle 6), 1-41 (2014).

CAY10774 is an inhibitor of the protein-protein interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 (IC50= 15 nM in a homologous time-resolved fret (HTRF) assay).1It increases the activation of Jurkat cells expressing PD-1 in co-culture with artificial antigen-presenting cells (aAPCs) expressing PD-L1 (EC50= 6.6 μM in a reporter assay). CAY10774 increases surface expression of PD-1 on primary human CD4+and CD8+T cells co-cultured with aAPCs. 1.Konieczny, M., Musielak, B., Kocik, J., et al.Di-bromo-based small-molecule inhibitors of the PD-1/PD-L1 immune checkpointJ. Med. Chem.63(19)11271-11285(2020)

LH1307 is an inhibitor of the interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 that has an IC50 value of 3 nM in a homologous time-resolved fluorescence (HTRF) assay.1 It increases the activation of Jurkat cells expressing PD-1 in co-culture with U2OS or CHO cells expressing PD-L1 (EC50s = 79 and 763 nM, respectively, in reporter assays). |1. Basu, S., Yang, J., Xu, B., et al. Design, synthesis, evaluation, and structural studies of C2-symmetric small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein-protein interaction. J. Med. Chem. 62(15), 7250-7263 (2019).

3,3'-((2-Chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) is a non-nucleotide inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; Ki = 50 μM).1,2 It also inhibits urease (IC50 = 84.53 μM for the Jack bean enzyme).3 |1. Choudhary, M.I., Fatima, N., Khan, K.M., et al. New biscoumarin derivatives-cytotoxicity and enzyme inhibitory activities. Bioorg. Med. Chem. 14(23), 8066-8072 (2006).|2. Onyedibe, K.I., Wang, M., and Sintim, H.O. ENPP1, an old enzyme with new functions, and small molecule inhibitors - A STING in the tale of ENPP1. Molecules 24(22), E4192 (2019).|3. Khan, K.M., Iqbal, S., Lodhi, M.A., et al. Biscoumarin: New class of urease inhibitors; economical synthesis and activity. Bioorg. Med. Chem. 12(8), 1963-1968 (2004).

BIO5192 hydrate is a selective and potent integrin α4β1 (VLA-4) inhibitor (Kd<10 pM). BIO5192 hydrate selectively binds to α4β1 (IC50=1.8 nM) over a range of other integrins. BIO5192 hydrate results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors (HSPCs) over basal levels[1][2]. The combination of BIO5192 hydrate (1 mg kg; i.v.) and Plerixafor (5 mg kg; s.c.) exert an additive effect on progenitor mobilization[1].BIO5192 hydrate (30 mg kg; s.c; bid; during days 5 through 14) delays paralysis associated with EAE (experimental autoimmune encephalomyelitis)[2].BIO5192 hydrate (1 mg kg, i.v.) shows the terminal half-life is 1.1 hours. BIO5192 hydrate (3, 10, and 30 mg kg; s.c.) shows half-lives of 1.7, 2.7, and 4.7 hours, respectively. The blood plasma curves show that the AUC for the s.c. route of administration increased about 2.5-fold from 5,460 h*ng ml for the 3 mg kg dose to 14,175 h*ng ml for the 30 mg kg[1]. Animal Model: C57BL 6J x 129Sv J F1 mice[1] [1]. Ramirez P, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood. 2009;114(7):1340‐1343. [2]. Leone DR, et al. An assessment of the mechanistic differences between two integrin alpha 4 beta 1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther. 2003;305(3):1150-1162.

CAY10727 is an inhibitor of protein arginine deiminase 3 (PAD3; kinact/KI= 15,600 M-1min-1).1It is selective for PAD3 over PAD1, -2, and -4 (kinact/KIs = 360, 1,110, and 1,460 M-1min-1, respectively). 1.Jamali, H., Khan, H.A., Stringer, J.R., et al.Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment methodJ. Am. Chem. Soc.137(10)3616-3621(2015)

CDK7 9 tide is peptide substrate for CDK7 or CDK9[1]. [1]. Robert T, et, al. Development of a CDK10 CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors. Front Chem. 2020 Feb 27; 8:147.

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

(Z)-4EGI-1 is the Z-isomer of 4EGI-1 and is an inhibitor of eIF4E eIF4G interaction and of translation initiation. (Z)-4EGI-1 effectively binds to eIF4E with an IC50 of 43.5 μM and a Kd value of 8.74 μM. (Z)-4EGI-1 has anticancer activity[1][2]. [1]. Khuloud Takrouri, et al. Structure-activity Relationship Study of 4EGI-1, Small Molecule eIF4E eIF4G Protein-Protein Interaction Inhibitors. Eur J Med Chem. 2014 Apr 22;77:361-77. [2]. Poornachandran Mahalingam, et al. Synthesis of Rigidified eIF4E eIF4G inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein-Protein Interaction. J Med Chem. 2014 Jun 26;57(12):5094-111.

Pantothenate Kinase Inhibitor (PANKi) is a reversible inhibitor of pantothenate kinase (PanK; IC50s = 70, 92, and 25 nM for PanK1β, PanK2, and PanK3, respectively), the rate-limiting enzyme in the synthesis of coenzyme A .1It binds to the ATP-PanK3 complex with an apparent binding constant of 300 nM and exhibits mixed-type inhibition with respect to ATP and pantothenate. PANKi inhibits CoA biosynthesis in C3A cells (IC50= 0.9 μM) with no effect on cell viability when used at concentrations up to 8 μM. PANKi (5 μM) synergizes with BSO to induce ferroptosis in PANC-1 cells and sensitizes the cells to imidazole ketone erastin-induced ferroptosis.2 1.Sharma, L.K., Leonardi, R., Lin, W., et al.A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinasesJ. Med. Chem.58(3)1563-1568(2015) 2.Badgley, M.A., Kremer, D.M., Maurer, H.C., et al.Cysteine depletion induces pancreatic tumor ferroptosis in miceScience368(6486)85-89(2020)

BX-320 is an inhibitor of the serine/threonine kinase 3-phosphoinositide-dependent protein kinase 1 (PDK1; IC50= 30 nM).1It is selective for PDK1 over a panel of 10 additional kinases (IC50s = >820 nM for all). BX-320 inhibits Akt and p70S6K1 phosphorylation in PC3 cells (IC50s = 1-3 μM). It induces apoptosis in, and inhibits the growth of, MDA-MB-468 breast cancer cells (IC50s = 0.5 and 0.6 μM, respectively), as well as inhibits cell growth in a panel of cancer cells (IC50s = 0.12-1.2 μM). BX-320 (200 mg/kg) inhibits the growth of lung tumors in a LOX melanoma mouse model of blood-borne metastasis. 1.Feldman, R.I., Wu, J.M., Polokoff, M.A., et al.Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1J. Biol. Chem.280(20)19867-19874(2005)

CAY10761 is an inhibitor of ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1; IC50s = 467 and 429 μM for the human and snake venom enzymes, respectively).1,2 It also inhibits mushroom tyrosinase (Ki = 1.9 μM) and urease from jack bean, P. mirabilis, and B. pasteurii (IC50s = 0.093, <0.125, and 0.089 mM, respectively, at pH 8.2).3,4 |1. Khan, K.M., Fatima, N., Rasheed, M., et al. 1,3,4-Oxadiazole-2(3H)-thione and its analogues: A new class of non-competitive nucleotide pyrophosphatases phosphodiesterases 1 inhibitors. Bioorg. Med. Chem. 17(22), 7816-7822 (2009).|2. Onyedibe, K.I., Wang, M., and Sintim, H.O. ENPP1, an old enzyme with new functions, and small molecule inhibitors - A STING in the tale of ENPP1. Molecules 24(22), E4192 (2019).|3. Ghani, U., and Ullah, N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site. Bioorg. Med. Chem. 18(11), 4042-4048 (2010).|4. Amtul, Z., Rasheed, M., Choudhary, M.I., et al. Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles thiadiazoles and triazoles. Biochem. Biophys. Res. Commun. 319(3), 1053-1063 (2004).

Talabostat (PT100, Val-boroPro) is a potent, nonselective and orally available dipeptidyl peptidase IV (DPP-IV) inhibitor with a Ki of 0.18 nM. Talabostat is a nonselective DPP-IV inhibitor, inhibiting DPP8/9, FAP, DPP2 and some other DASH family enzymes essentially as potently as it inhibits DPP-IV[1]. Talabostat stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. The inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC[2]. Talabostat competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26/DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser630/624 and the boron of talabostat[3]. Talabostat can stimulate immune responses against tumors involving both the innate and adaptive branches of the immune system. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 causes regression and rejection of tumors. The antitumor effect appears to involve tumor-specific CTL and protective immunological memory. Talabostat treatment of WEHI 164-inoculated mice increases mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells[3]. Talabostat treated mice show significant less fibrosis and FAP expression is reduced. Upon PT100 treatment, significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs are also observed. Treatment with PT100 in this murine model of pulmonary fibrosis has an anti-fibro-proliferative effect and increases macrophage activation[4]. [1]. Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13. [2]. Okondo MC, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [3]. Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80. [4]. Egger C, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017 Aug 15;809:64-72.

Tunlametinib是高选择性口服MEK1/MEK2激酶抑制剂（对MEK1的IC50为1.9 nM），通过阻断RAS-RAF-MEK-ERK致癌信号通路诱导肿瘤细胞周期阻滞与凋亡。对BRAF V600E或KRAS G12C等突变型肿瘤细胞具有强抑制活性，与BRAF/KRASG12C/SHP2抑制剂及多西他赛（Docetaxel）联用呈现协同效应，目前已应用于黑色素瘤、结直肠癌及非小细胞肺癌等RAS/RAF驱动型肿瘤的靶向治疗。

SRI 31215 TFA 是 matriptase、hepsin、肝细胞生长因子激活剂(HGFA)的三重抑制剂，IC50值分别为 0.69 μM、0.65 μM、0.3 μM。它能够阻断 pro-HGF 的活化，模拟 HAI-1 2 的活性。

Glomeratose A 是分离自远志Polygala tenuifolia 中，是一种乳酸脱氢酶lactate dehydrogenase 抑制剂。

Blapsin B is a potent 14-3-3 inhibitor. Blapsin B is a naturally occurring compound isolated from the ethanol extract of the stink beetle, Blaps japanensis. Blapsin B potently inhibited 14-3-3 protein-protein interactions (PPIs) with IC(50) value of 10.0 μM as determined by an ELISA assay, and 2.5 μM in an FP assay, respectively. Blapsin B represent the first example of natural small-molecule 14-3-3 inhibitors.

Olmutinib (HM61713, BI 1482694) 是可口服的不可逆 EGFR 酪氨酸激酶抑制剂，其与激酶结构域附近的半胱氨酸残基结合，可用于非小细胞肺癌的研究。