microenvironment

Osunprotafib (ABBV-CLS-484) is a potent, orally bioavailable PTP1B PTPN2 inhibitor in clinical trials for solid tumors. [1] Osunprotafib (ABBV-CLS-484) stimulates the tumor microenvironment and promotes natural killer cell and CD8 T cell function and enhances T cell anti-tumor immunity by enhancing JAK-STAT signaling and reducing T cell dysfunction. [2]

Polyinosinic-polycytidylic acid sodium (Poly(I:C) sodium) is a synthetic analog of double-stranded RNA and an agonist of toll-like receptor 3 (TLR3) and retinoic acid inducible gene I (RIG-I)-like receptors (RIG-I and MDA5).

Ibuprofen (Advil) is a propionic acid derivate and nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Ibuprofen inhibits the activity of cyclo-oxygenase I and II, resulting in a decreased formation of precursors of prostaglandins and thromboxanes.

Sodium dichloroacetate (BCA) , a specific inhibitor of pyruvate dehydrogenase kinase (PDK) with IC50 values of 183 and 80 μM for PDK2 and PDK4 respectively, has been shown to derepress a mitochondrial potassium-ion channel axis, trigger apoptosis in cancer cells, and inhibit tumor growth.

Crenigacestat (LY3039478) is an orally bioavailable Notch inhibitor with an IC50 of ~1 nM in most tumor cell lines tested. It effectively inhibits mutant Notch receptor activity and, in a xenograft tumor model, inhibits the expression of Notch-regulated genes and N1ICD cleavage in the tumor microenvironment.

MTI-31 (LXI-15029) is a potent, orally active, and highly selective inhibitor of mTORC1 and mTORC2, exhibiting a Kd of 0.20 nM for mTOR and >5,000-fold selectivity over PIK3CA, PIK3CB, and PIK3G in binding assays, with an IC50 of 39 nM for mTOR in a LANCE assay of mTOR substrate phosphorylation with 100 μM ATP [1].

CCR4 antagonist 2 (Compound 31) is a novel, potent, orally bioavailable small molecule antagonist of CC chemokine receptor 4 (CCR4) that inhibits Treg trafficking into the Tumor Microenvironment without suppressing the number of Treg in healthy tissues. CCR4 antagonist 2 (Compound 31) exhibits IC50 values of Ca2+ flux and [chemotaxis] CTX at 40 nM and 70 nM, respectively.

Sitravatinib malate is an orally bioavailable receptor inhibitor of tyrosine kinase (RTK) (IC50s of 1.5 nM, 2 nM, 2 nM, 5 nM, 6 nM, 6 nM, 8 nM, 0.5 nM, 29 nM, 5 nM, and 9 nM for Axl, MER, VEGFR3, VEGFR2, VEGFR1, KIT, FLT3, DDR2, DDR1, TRKA, TRKB, respectively.) , shows potent single-agent antitumor efficacy and enhances the activity of PD-1 blockade through promoting an antitumor immune microenvironment.

AlbA-DCA, a conjugate of Albiziabioside A and a dichloroacetate acid subunit, markedly increases intracellular ROS, alleviates lactic acid accumulation in the tumor microenvironment, selectively kills cancer cells, and induces apoptosis.

CL2A-SN-38 consists of a CL2A linker and an anticancer compound, SN-38, which delivers active molecules within tumor cells and in the tumor microenvironment, often in conjunction with antibodies to make biologically active antibody-coupled reactive molecules (ADCs).

CL2A-SN-38 (GMP) refers to the GMP grade reagents of CL2A-SN-38. CL2A-SN-38 consists of a CL2A linker and an anticancer compound, SN-38, which delivers active molecules within tumor cells and in the tumor microenvironment, often in conjunction with antibodies to make biologically active antibody-coupled reactive molecules (ADCs).

Nic-15 (compound 4n) serves as an anti-constrictive agent targeting the low vascular characteristics of pancreatic tumors. These characteristics enable cancer cells to adapt to the nutrient-deficient tumor microenvironment and develop resistance to treatment. Nic-15 modulates the PI3K Akt mTOR pathway and alleviates ER stress induced by Gemcitabine. It significantly inhibits migration and colony formation in MIA PaCa-2 and PANC-1 pancreatic cancer cells. When used in combination with Gemcitabine, Nic-15 effectively addresses resistance issues in pancreatic tumors. In xenograft models in vivo, Nic-15 notably enhances the efficacy of Gemcitabine.

Compound 3, known as 5-LOX MAOs-IN-1, acts as an inhibitor of 5-LOX MAOs and is an effective free radical scavenger, displaying antioxidant characteristics. It has demonstrated neuroprotective effects in cell models damaged by oxidative stress and is capable of activating the neurogenesis microenvironment in adult mouse neural stem cells. This compound is utilized in research focused on neurodegenerative diseases.

SJ-C1044 is an orally effective pan-RAF inhibitor demonstrating immunomodulatory and antitumor activities. It targets wild-type BRAF, wild-type CRAF, and BRAF(V600E) with IC50 values of 331, 257, and 187 nM, respectively. SJ-C1044 suppresses tumor cell proliferation by inhibiting kras activation and MEK-ERK phosphorylation. Additionally, it shows inhibition of VEGFR2, TIE2, and CSF1R, with IC50 values of 100, 23, and 235 nM respectively. The compound enhances the tumor immune microenvironment through inhibition of angiogenesis and modulation of macrophage function. SJ-C1044 is applicable for research in colorectal cancer.

DNMT1 HDAC-IN-1 (compound (R)-23a), a potent dual inhibitor targeting both DNMT1 and HDAC, exhibits impressive inhibitory effects specifically on HDAC1 (HDAC1:IC50=0.05 μM), a major HDAC isoform that interacts with DNMT1 across multiple protein complexes involved in the transcriptional silencing of TSGs. This compound has been shown to remodel the tumor immune microenvironment and induce tumor regression, effectively reversing cancer-specific epigenetic abnormalities.

Bleomycin A6 (also known as boanmycin) is utilized in trials for treating squamous cell lung cancer. Studies indicate that Bleomycin A6 not only exhibits antitumor effects but also modifies the tumor microenvironment, which may contribute to the recurrence and metastasis of lung cancer during prolonged treatment.

PF-07265028 is an HPK1 inhibitor with an IC50 of 17 nM. Pharmacokinetic studies in mice and monkeys indicate that PF-07265028 exhibits moderate clearance, terminal half-life, volume of distribution, and oral bioavailability. It targets, binds, and inhibits Hpk1 activity, blocking Hpk1-mediated signaling pathways to prevent immune suppression mediated by Hpk1, including the inhibition of T-cell receptor (TCR) signaling, effector T-cell suppression, aberrant cytokine expression, and the elimination of the immunosuppressive tumor microenvironment (TME). This action can activate a cytotoxic T lymphocyte (CTL)-mediated immune response against tumor cells. Hpk1 is primarily expressed in hematopoietic cells and acts as a negative regulator of TCR signaling and T and B cell activation.

DTS-201 sodium (CPI-0004Na) is a peptide prodrug of Doxorubicin. It contains a tetrapeptide segment that is hydrolyzed by endopeptidases in the tumor microenvironment to produce metabolites, which are then converted into active Doxorubicin upon cellular entry. DTS-201 has demonstrated antitumor efficacy in xenograft models of prostate, breast, and lung cancers.

ZSA-51 is an effective, orally active STING agonist with anticancer properties. It has the capability to remodel the immune microenvironment within tumors and lymph nodes.

TLR7 agonist 29 (Compound 1) is an activator of TLR7, displaying an EC50 of 5.2 nM for human TLR7 and 48.2 nM for mouse TLR7. It can activate bone marrow-derived macrophages (BMDM) and stimulate myeloid cells within the tumor microenvironment, enhancing the expression of PD-L1, CD86, and IFN-α. Additionally, TLR7 agonist 29 can serve as a payload for synthesizing ADCs.

Enpp-1-IN-25 (Compound 30) is an ENPP1 inhibitor with an IC50 of 8.05 nM and exhibits low oral bioavailability. By inhibiting cGAMP degradation, it effectively activates the intracellular STING pathway. Enpp-1-IN-25 can enhance immune cell infiltration and type I interferon response in the tumor microenvironment, thereby increasing the antitumor efficacy of anti-PD-L1 antibodies. It is applicable for research in cancer immunotherapy.

PD-L1 HDAC-IN-1 (Compound 14) is an inhibitor of PD-L1 and HDAC, effectively blocking PD-1 PD-L1 interaction as well as HDAC2 and HDAC3 with IC50 values of 88.10, 27.98, and 14.47 nM, respectively. It exhibits mild cytotoxicity in MCF-7 cells (IC50=19.34 μM) and enhances the expression of PD-L1 and CXCL10, promoting antitumor immune responses by recruiting T cell infiltration into the tumor microenvironment (TME).

SHP2-IN-35 (Compound 3f) functions as an inhibitor of SHP2. It exhibits antiproliferative activity in cancer cell lines RKO, SW480, and CT26, with IC50 values of 5.72 μM, 3.71 μM, and 1.42 μM, respectively. SHP2-IN-35 inhibits the PI3K-Akt signaling pathway, regulates the expression of cell cycle-related genes, and induces mitochondrial autophagy (autophagy). Within the tumor microenvironment (TME), SHP2-IN-35 suppresses the expression of certain cytokines and chemokines, thereby modulating tumor progression.

PD-L1 VISTA-IN-2 (Compound S8) is an orally active dual inhibitor targeting PD-L1 and VISTA, with an IC50 of 1.4 μM for PD-L1 and a KD of 2.1 μM for VISTA. This compound can activate the tumor immune microenvironment, exerting anticancer effects.