pk-1

DNA-PK-IN-1, a potent inhibitor of DNA-PK, holds potential for cancer disease research.

Kemptide TFA is a synthetic heptapeptide, acting as a substrate for cAMP-dependent protein kinase (PK).

Atabecestat (JNJ-54861911) is a potent, brain-penetrant, and orally active β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor that achieves robust and high CSF Aβ reduction, is well-tolerated, and displays sustained pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. Atabecestat (JNJ-54861911) has the potential for Alzheimer's Disease treatment[1].

PK11000 is a p53 targeting compound, has anti-tumor activities through activation of unstable p53.

OSI-027 (ASP4786) is a selective and potent dual inhibitor of mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, and more than 100-fold selectivity observed for mTOR than PI3Kα, PI3Kβ, PI3Kγ or DNA-PK. Phase 1.

Voxtalisib (XL765) (SAR245409, XL765) is a dual inhibitor of mTOR PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1 2.

YM44781 is a non-peptide tachykinin receptor antagonist. YM44781 exhibits high binding affinities at NK(1) (pK(i) = 9.09 +/- 0.02) and NK(2) (pK(i) = 9.94 +/- 0.03) receptors, respectively.

Fosnetupitant chloride monohydrochloride (Pro-netupitant chloride monohydrochloride) is a selective NK1 antagonist exhibiting high affinity for the human NK1 receptor with a pK i value of 9.5, and a lower affinity for the NK3 receptor with a pK i of 6.1. It serves as a methylene phosphate prodrug of Netupitant [1].

IDO1-IN-22 (Compound 3) is an inhibitor of IDO1 with potent activity, showing a biochemical hIDO1 IC50 of 67.4 nM and HeLa hIDO1 IC50 of 17.6 nM. It demonstrates excellent antitumor efficacy in an LLC xenograft model and has a desirable pharmacokinetic (PK) profile [1].

LmCPB-IN-1 (compound 35) is a highly effective and reversible covalent inhibitor of Leishmania mexicana cysteine protease B (LmCPB), exhibiting a strong binding affinity with a pK i value of 9.7 [1].

DNA-PK-IN-3 is a highly potent inhibitor of DNA-PK that exerts a synergistic effect with radiotherapy and chemotherapy, enhancing therapeutic outcomes and significantly inhibiting tumor growth. Additionally, it demonstrates remarkable efficacy in reducing damage to normal cells, thereby minimizing adverse side effects, making it a compound of great potential for cancer research applications[1].

BAY-707, a highly potent and selective substrate-competitive inhibitor of MTH1 (NUDT1) with an IC50 of 2.3 nM, is well-tolerated in mice and exhibits a favorable pharmacokinetic (PK) profile compared to other MTH1 compounds. However, it demonstrates a clear lack of anticancer efficacy both in vitro and in vivo[1].

AZ8838 is an effective, competitive, allosteric, orally active non-peptide small molecule antagonist of PAR2 with a pK i of 6.4 for hPAR2 [1].

PKItide demonstrates an inhibitory concentration 50 (IC50) of 0.2 μM against cAMP-dependent protein kinase (cAMP-PK) [1].

NNMT-IN-4 (compound 38) is a selective, uncompetitive inhibitor of nicotinamide N-methyltransferase (NNMT) with in vitro biochemical and cell-based assay IC50 values of 42 nM and 38 nM, respectively. It demonstrates favorable pharmacokinetics pharmacodynamics (PK PD) and safety profiles, excellent oral bioavailability, and promising pharmaceutical properties. NNMT-IN-4 serves as an in vivo chemical probe for NNMT [1].

DNA-PK-IN-2 is a highly effective inhibitor of DNA-dependent protein kinase (DNA-PK), an enzyme complex comprising the Ku70 Ku80 heterodimer and DNA-PK catalytic subunit (DNA-PKcs). It shows potential applications in cancer research, making it a valuable tool for studying cancer diseases [1].

CE-245677 is a selective, orally active Tie2 kinase inhibitor identified by Pfizer previously in development for the treatment of certain cancers. CE-245,677 is a potent reversible inhibitor of Tie2 and TrkA/B kinases with a cellular IC50 of 4.7 and 1 nM, resp., displays >100x selectivity against a number of other angiogenic receptor tyrosine kinases (e.g. KDR, PDGFR, FGFR) and gene family panels, and demonstrates good oral absorption in in vivo rat PK studies (F=80%).

LY3325656 is a GPR142 agonist suitable for clinical testing in human. LY3325656 demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. LY3325656 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.

ZL-2201 is a potent inhibitor of DNA-PK, demonstrating an IC50 value of 1 nM.

Yhhu6669 is an anti-HBV agent that suppresses viral DNA and replication by promoting DNA-free capsid assembly, effectively reducing HBV DNA and HBcAg levels in AAV/HBV-infected mice and demonstrating favorable pharmacokinetic (PK) properties [1].

UNC5293 is a potent, orally available and highly MERTK-selective inhibitor with Ki of 190 pM. UNC5293 inhibits MERTK ( IC 50 =0.9 nM) and is more selective over Axl, Tyro3 and Flt3. UNC5293 exhibits excellent mouse PK properties and is used for bone marrow leukemia research [1].

DNA-PK-IN-8 is a potent, selective, and orally active inhibitor of DNA-dependent protein kinase (DNA-PK) with an IC50 value of 0.8 nM, demonstrating synergistic antiproliferative effects across various cancer cell lines and significantly reducing HL-60 tumor growth when combined with Doxorubicin [1].

Pasireotide diaspartate (SOM230), a long-acting cyclohexapeptide and somatostatin analog, enhances agonist activity across somatostatin receptor subtypes (sst1/2/3/4/5, with pK i values of 8.2, 9.0, 9.1, <7.0, and 9.9, respectively). This compound demonstrates antisecretory, antiproliferative, and proapoptotic activities [1] [2].

Canfosfamide (TLK-286, TER286), a glutathione analogue prodrug, becomes activated by glutathione S-transferase P1-1 to induce apoptosis and inhibit DNA-dependent protein kinase's (DNA-PK) catalytic kinase activity. Upon activation, it generates an anticancer alkylating agent and a glutathione derivative, making it useful in researching malignancies [1] [2] [3].

GR 94800 TFA is a potent, selective antagonist of the NK 2 receptor peptide, demonstrating pK B values of 9.6 for NK 2, 6.4 for NK 1, and 6.0 for NK 3 receptors, respectively [1] [2].

ATV041, an orally active compound that combines features of Ibuprofen and nucleotide analogues, enhances the oral pharmacokinetic (PK) profile and tissue distribution, exhibiting anti-mouse hepatitis virus (MHV) activity. The compound demonstrates a dose-dependent reduction in viral load, tissue damage, and virus-induced inflammation [1].

QLT0267 is an inhibitor targeting integrin-linked kinase (ILK; IC50= 26 nM), showing over 10-fold selectivity against cyclin-dependent kinases 1, 2, and 5 (Cdk1, Cdk2, and Cdk5), and over 1,000-fold selectivity against C-terminal Src kinase (CSK), DNA-PK, Pim-1, Akt, PKC, and casein kinase 2 (CK2) at a concentration of 10 mg/ml. This compound effectively inhibits the proliferation of NPA187 papillary thyroid cancer cells with an IC50 of approximately 3 µM and induces apoptosis in NPA187, DRO, and K4 cancer cell lines. In vivo studies reveal that QLT0267, administered at 100 mg/kg, significantly reduces tumor growth in a DRO mouse xenograft model and diminishes both tumor volume and intratumoral vascularization in a U87MG glioblastoma mouse xenograft model, showcasing its potential for therapeutic applications in cancer treatment.

PI3K-IN-1 (Voxtalisib Analogue) is a dual inhibitor of mTOR/PI3K, mostly for p110γ , also inhibits DNA-PK and mTOR.

ROS 234 is a highly effective H3 antagonist, demonstrating a strong binding affinity (pK B) of 9.46 for the Guinea-pig ileum H3 receptor and a pKi of 8.90 for the Rat cerebral cortex H3 receptor. Additionally, it exhibits an ex vivo ED50 of 19.12 mg/kg (ip) in the Rat cerebral cortex. It should be noted that ROS 234 demonstrates limited central access, as reported in [1] and [2].

PK-10, when combined with Fluconazole, exhibits potent synergistic antifungal activity against multiple Fluconazole-resistant Candida albicans strains. This compound impedes hyphae formation, stimulates reactive oxygen species accumulation, and inflicts mitochondrial membrane potential damage. Consequently, PK-10 decreases cellular ATP levels and induces mitochondrial dysfunction [1].

DNA-PK-IN-10 is a DNA-PK inhibitor used in breast cancer and non-small cell lung cancer research [1].

ATR-IN-15 (compound 1) is a highly potent, orally active ATR kinase inhibitor with an IC50 of 8 nM. It also exhibits inhibitory activity against human colon tumor cells LoVo, DNA-PK, and PI3K, with IC50 values of 47, 663, and 5131 nM, respectively [1].

Tuberculosis inhibitor 3 (compound 2i) exhibits potent anti-TB properties (MIC < 0.016 μg mL) against both drug-sensitive and resistant MTB strains, with acceptable pharmacokinetic profiles and oral bioavailability[1].

DNA-PK-IN-6, a robust DNA-PK inhibitor, effectively hampers the activity of DNA-PKcs, thereby significantly impairing the DNA repair mechanism in tumors and instigating apoptosis in cells. Additionally, DNA-PK-IN-6 amplifies the responsiveness of tumor tissues to radiotherapy, overcomes the challenge of drug resistance, and augments its inhibitory impact on a diverse range of solid and hematological tumors[1].

DNA-PK-IN-9 (also known as compound YK6) is a highly potent inhibitor of DNA-dependent protein kinase (DNA-PK), displaying an IC50 value of 10.47 nM. DNA-PK-IN-9 holds significant potential in anticancer research [1].

GR 83074 is a potent and selective antagonist of the NK-2 (Neurokinin Receptor) with a 340-fold selectivity over NK-1 and a pK_B value of 8.23. It does not act as an antagonist for NK-3, affirming its specificity [1].

DNA-PK-IN-4 (WO2021209055A1, compound 27), an imidazolinone derivative compound, is a highly effective inhibitor of DNA-PK, specifically targeting DNA-PKcs activity. By inhibiting DNA-PKcs, the compound significantly impairs tumor DNA repair mechanisms and triggers apoptosis in cells. With its potential application in cancer research, DNA-PK-IN-4 holds promise for further investigation [1].

BAY-8400 is a potent, selective, and orally active DNA-dependent protein kinase (DNA-PK) inhibitor (IC50 = 81 nM) that demonstrates synergistic efficacy when combined with targeted alpha therapies. BAY-8400 is applicable for cancer research [1].

AR-C141990 hydrochloride is a potent inhibitor of lactate transporters known as monocarboxylate transporters (MCTs), with pK i values of 7.6 and 6.6 for MCT-1 and MCT-2, respectively. This compound also exhibits immunosuppressive properties and effectively inhibits the graft versus host response.

Etedesiran acts as an inhibitor of Myotonin-protein kinase (MT-PK, MDPK, or DMPK) [1].

LEI-101 is a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist, with a pEC50 of 8 for hCB2, and a pKi of less than 4 for hERG. LEI-101 is approximately 100-fold more potent in binding to CB2 receptors than to CB1 receptors. It has therapeutic potential in diseases associated with inflammation and or oxidative stress, including kidney disease [1] [2].

TrkB-IN-1 is a potent, orally active agonist of the TrkB receptor, with favorable pharmacokinetic (PK) properties. It has been shown to reverse cognitive deficits in an Alzheimer's disease (AD) mouse model, thus serving as a valuable tool for Alzheimer’s disease research [1].

PLX5622 hemifumarate is a highly selective, brain-penetrant, and orally active CSF1R inhibitor with an IC50 of 0.016 μM and Ki of 5.9 nM. It allows for extended and specific microglial elimination preceding and during pathology development and demonstrates desirable PK properties in various animals [1] [2].

Mitapivat (PKR-IN-1), also known as PKM2 activator 1020 is a PKM2 activator (pyruvate kinase activator) for the treatment of pyruvate kinase deficiency.

SRA880 is a non-peptide somatostatin sst(1) receptor antagonist which displays a significantly lower affinity for the other human recombinant somatostatin receptors ( pK(d)= 6.0) or a wide range of neurotransmitter receptors, except for the human dopamine

Abraxane (nab-Paclitaxel) is an albumin-bound formulation of Paclitaxel nanoparticles known for its enhanced response rates and tolerability. Leveraging albumin as a delivery vehicle, this compound achieves a favorable pharmacokinetic (PK) profile [1] [2].

Irpagratinib (ABSK011) is an orally active fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with specificity for FGFR4, exhibiting an IC50 of less than 10 nM. It effectively inhibits FGFR4 auto-phosphorylation and disrupts subsequent signal transduction to downstream pathways. Demonstrating high exposure in pharmacokinetic studies in mice, rats, and dogs, Irpagratinib also displays antineoplastic activity in subcutaneous xenograft tumor models [1].

PK68 is an effective and selective inhibitor of type II receptor-interacting kinase 1 (RIPK1, IC50 = 90 nM). PK68 can be used for research on the treatment of inflammatory disorders and cancer metastasis.

BPN-15606, an orally active γ-secretase modulator (GSM), significantly reduces Aβ42 and Aβ40 production in SHSY5Y neuroblastoma cells, demonstrating IC50 values of 7 nM and 17 nM, respectively. This compound exhibits favorable pharmacokinetic/pharmacodynamic (PK/PD) properties, such as bioavailability, half-life, and clearance. Importantly, BPN-15606 markedly decreases Aβ42 and Aβ40 levels in the central nervous system of both rats and mice[1].

YM49598 is a tachykinin receptor antagonist. YM49598 exhibited high binding affinities at NK(1) (pK(i) = 9.09 +/- 0.02) and NK(2) (pK(i) = 9.94 +/- 0.03) receptors, respectively. YM49598 was almost inactive but produced a potent inhibition (IC(50) = 11 +/