h1975

TAS6417 is an EGFR inhibitor and is an efficacious drug candidate for patients with NSCLC (IC50: ranging from 1.1-8.0 nM).

Osimertinib (AZD-9291) is an EGFR third-generation inhibitor that inhibits the T790M resistance mutation produced by second-generation EGFR inhibitors with irreversible and oral activity. Osimertinib has antitumor activity for the treatment of EGFR-mutated non-small-cell lung cancer.

EGFR-IN-1 hydrochloride is an irreversible and specific inhibitor of L858R/T790M mutant EGFR with 100-fold selectivity over wild-type EGFR. EGFR-IN-1 hydrochloride exhibits potent antitumor and antiproliferative activity in H1975 cells and the mutant HCC827 cells with IC50s of 4 and 28 nM, respectively.

OTUB1/USP8-IN-1 is a potent OTUB1/USP8 inhibitor with potential anticancer activity, with IC50 values of 0.17 and 0.28 nM for OTUB1 and USP8, respectively.OTUB1/USP8-IN-1 can be used in the study of non-small-cell lung cancer.

PF-06459988 is a novel, effective, orally active, irreversible, and selective epidermal growth factor receptor (EGFR) mutant inhibitor. PF-06459988 has high efficiency and high affinity for EGFRs double mutants containing T790M, and has minimal activity against WT EGFR. PF-06459988 makes a candidate drug for the treatment of cancer.

Osimertinib mesylate (Mereletinib mesylate) is an irreversible and mutant selective EGFR inhibitor (IC50s: 12/1 nM for EGFR(L858R) and EGFR(L858R/T790M)).

Afatinib Dimaleate (BIBW 2992MA2) is an orally bioavailable anilino-quinazoline derivative and inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity.

Afatinib (BIBW 2992) is an irreversible inhibitor of EGFR family (EGFR-wt, EGFR-L858R, EGFR-L858R/T790M and HER2 with IC50s of 0.5 nM, 0.4 nM, 10 nM and 14 nM , respectively).

PROTAC EGFR degrader 8 (T-184) is a PROTAC that selectively degrades the epidermal growth factor receptor (EGFR) with a DC50 of 15.56 nM in HCC827 cells. It effectively inhibits the growth of various cell lines, including H1975, PC-9, and HCC827, with IC50 values of 7.72 nM, 121.9 nM, and 14.21 nM, respectively. This compound is primarily used for cancer research, particularly in the context of non-small cell lung cancer (NSCLC) [1].

EGFR-IN-90 (compound 34), an orally active EGFR inhibitor, demonstrates potent activity against EGFRL858R/T790M/C797S with an IC50 of 5.1 nM and effectively inhibits the proliferation of the H1975-TM cell line carrying EGFRL858R/T790M/C797S mutations with an IC50 of 0.05 μM. Additionally, EGFR-IN-90 suppresses tumor growth in the H1975-TM xenograft tumor model [1].

PROTAC EGFR degrader 4 is a potent molecule designed to target and degrade mutant EGFR, showcasing its effectiveness by inducing degradation of EGFR del19 and EGFR L858R/T790M with DC50 values of 0.51 nM and 126 nM, respectively. Furthermore, it significantly inhibits the growth of HCC827 and H1975 cell lines, demonstrating IC50 values of 0.83 nM and 203.1 nM, respectively. The induced degradation of EGFR by this compound is associated with autophagy [1].

PROTAC EGFR Degrader 3, a highly potent molecule, exhibits remarkable cellular activity against H1975 and HCC827 cells, maintaining high selectivity. It additionally reveals the lysosome's crucial role in the degradation mechanism of mutant EGFR [1].

2-Desoxy-4-epi-pulchellin has potent in vitro cytotoxicities against the K562, MCF-7, Hela, DU145, U937, H1975, SGC-7901, A549, MOLT-4, and HL60 cell lines with IC50 values ranging from 0.10 to 46.7uM, while it shows significant antiviral (H1N1 and H3N2) activities, it also displays significant antimycobacterial activity (IC50=7.6 uM).

Anticancer agent 154 (Compound 8h) enhances reactive oxygen species production, causing mitochondrial damage, and promotes cell apoptosis and DNA damage. It triggers ferroptosis by depleting GSH, diminishing GPX4 expression, and escalating lipid peroxidation. Furthermore, it effectively suppresses the proliferation of various cancer cells (HT29, H1975, A549, and MCF-7) with IC50 values ranging from 1.0 to 1.9 μM [1].

PROTAC EGFR degrader 7 (compound 13b) is a potent, selective, CRBN-recruiting EGFRL858R/T790M degrader with a DC50 of 13.2 nM. It effectively inhibits proliferation of NCI-H1975 cells with an IC50 of 46.82 nM, induces apoptosis, and causes a G2/M phase arrest in these cells. Demonstrating antitumor activity, this compound is applicable in non-small cell lung cancer (NSCLC) research.

PROTAC EGFR degrader 7 (compound 13b) is a potent, selective CRBN-recruiting agent targeting EGFR L858R/T790M mutations with a DC50 of 13.2 nM. It effectively inhibits proliferation in NCI–H1975 cells with an IC50 of 46.82 nM and significantly triggers apoptosis and G2/M phase arrest in these cells. Demonstrating antitumor efficacy, PROTAC EGFR degrader 7 holds promise for non-small cell lung cancer (NSCLC) research [1].

Panitumumab is a fully human IgG2 monoclonal antibody targeting the epidermal growth factor receptor EGFR).

HDAC6/HSP90-IN-1 is a potent and selective dual inhibitor of HDAC6 (IC50: 4.3 nM) and HSP90 (IC50: 46.8 nM).HDAC6/HSP90-IN-1 downregulates PD-L1 expression in INF-γ-treated H1975 lung cancer cells.HDAC6/HSP90-IN-1 exhibits tumor growth inhibition in H1975 xenograft mice.HDAC6/HSP90-IN-1 is a potent and selective dual inhibitor of HDAC6 (IC50: 4.3 nM) and HSP90 (IC50: 46.8 nM). 1 exhibited tumor growth inhibition in H1975 xenograft mice.

WZ8040 is a novel mutant-selective irreversible EGFRT790M inhibitor, does not inhibit ERBB2 phosphorylation (T798I).

Antiproliferative Agent-34 (Compound A14), a multitarget kinase inhibitor, demonstrates IC50 values of 177 nM for EGFR L858R/T790M and 1567 nM for EGFR WT. Additionally, it inhibits JAK2, ROS1, FLT3, FLT4, and PDGFRα with respective IC50s of 30.93 nM, 106.90 nM, 108.00 nM, 226.60 nM, and 42.53 nM. In normoxic conditions, it suppresses the proliferation of H1975 and HCC827 cells with IC50 values below 40 nM, while under hypoxic conditions, its potency increases 4-6 fold, yielding IC50 values less than 10 nM [1].

ALK/EGFR-IN-2 is a potent dual inhibitor targeting ALK and EGFR, promoting apoptosis and G0/G1 cell cycle arrest in cancer cells. It effectively suppresses proliferation in H1975, PC9, and Baf3-EML4-ALK cancer cell lines, demonstrating IC50s of 0.0034, 0.0065, and 0.0018 μM, respectively [1].

Flavokawain 1i, a derivative of chalcones flavokawain A, flavokawain B, and flavokawain C, exhibits anticancer and antiviral properties. At a concentration of 30 µM, it suppresses the growth of gefitinib-resistant H1975 non-small cell lung cancer (NSCLC) cells by 36% and modulates the protein expression by reducing the levels of heat shock protein 90 (Hsp90) client proteins, including EGFR, c-Met, HER2, Akt, and cyclin-dependent kinase 4 (Cdk4), while increasing the levels of Hsp70, indicative of Hsp90 inhibition. Additionally, intramuscular injection of flavokawain 1i lowers viral loads in pigs afflicted with porcine reproductive and respiratory syndrome virus (PRRSV).

DM-CO-(CH2)5-SMe, derived from an antibody-drug conjugate (ADC) metabolite, serves as an anticancer agent with demonstrated cytotoxicity against H1703, H1975, COLO704, and Colo720E cells [1].

ALK/EGFR-IN-1 (Compound 8l) is a dual inhibitor targeting both ALK and EGFR, effectively blocking their phosphorylation. It demonstrates potent inhibition of ALK/EGFR mutants with IC50 values of 4.3 nM for EGFR L858R T790M in H1975 cells and 3.6 nM for EML4-ALK in BaF3 cells. This compound may be applicable in the research of non-small cell lung cancer (NSCLC) [1].

EGFR-IN-61 (compound 22a), a potent EGFR kinase inhibitor, exhibits IC50 values of 42 nM for L858R/T790M, 137 nM for L858R/T790M/C797S, and 743 nM for WT. Additionally, it demonstrates antiproliferative activity against the A549 and H1975 cell lines, with IC50 values of 2.14 μM and 1.82 μM, respectively [1].

EGFR-IN-62 is a potent inhibitor of EGFR kinase with IC50 values of 10 nM for L858R/T790 M, 29 nM for WT and 2 42 nM for L858R/T790 M/C797S. EGFR-IN-62 blocks the cell cycle of A549 and/or H1975 cells in G1/G0 phase and induces apoptosis and motility inhibition. EGFR-IN-62 effectively inhibited the proliferation of A549 (IC50: 2.53 μM) and H1975 cells (IC50: 1.56 μM).

Tubulin/AKT1-IN-1 (Compound D1-1) serves as an inhibitor of both tubulin polymerization and AKT pathway activation, effectively suppressing proliferation and metastasis of H1975 cells while modestly inducing apoptosis. This compound is utilized in the study of non-small-cell lung cancer (NSCLC) [1].

ALK/EGFR-IN-3 is a dual ALK and EGFR inhibitor that demonstrates potent anti-proliferative effects on various cancer cell lines, including H1975, PC9, and Baf3-EML4-ALK, with respective IC50 values of 0.1360, 0.0332, and 0.0339 μM [1].

EGFR-IN-60 is an effective, orally active, safe antitumor agent. EGFR-IN-60 significantly inhibits EGFRWT (IC50: 83 nM), EGFRT790M (IC50: 26 nM), EGFRL858R (IC50: 53 nM) and JAK3 (IC50: 69 nM). IN-60 inhibited H1975 cells carrying the EGFRT790M mutation (IC50: 1.32 μM) and A431 cells overexpressing EGFRWT (IC50: 4.96 μM). EGFR-IN-60 increased the Bax/Bcl-2 ratio, which induced apoptosis induction and cell death.

EGFR-IN-55 is a potent inhibitor of EGFR, acting on EGFRWT (IC50: 70 nM) and EGFRL858R/T790M (IC50: 3.9 nM). EGFR-IN-55 was able to block the cell cycle of NCI-H1975 cells in G0/G1 phase, exhibiting anticancer effects.

ASK120067 is a potent and orally active inhibitor of EGFRT790M (IC50:0.3 nM) with selectivity over EGFRWT (IC50:6.0 nM). ASK120067 is a third-generation EGFR-TKI for the research of non-small cell lung cancer (NSCLC)[1]. In the in vitro kinase assay ASK120067 potently inhibits the EGFR L858R/T790M and EGFR T790M resistant mutants with IC50 values of 0.3 nM and 0.5 nM, respectively, as well as the EGFRexon19del sensitizing mutant (IC50= 0.5 nM). The 50 of ASK120067 against wild-type EGFR (EGFRWT) is 6 nM[1].ASK120067 selectively inhibits the growth of EGFR-mutant cell lines and exhibits potent antiproliferative activity in the mutant EGFR NSCLC cells, with IC50 values of 12 nM, 6 nM and 2 nM against NCI-H1975 (T790M mutation), PC-9, and HCC827 cells (sensitizing mutations), respectively. However, it shows moderate or weak anti-growth activities in A431, LoVo and A549 cells (EGFRWT), with IC50 values ranging from 338 nM to 1541 nM[1].ASK120067 (0.1-100 nM) inhibits the phosphorylation of EGFR at Tyrosine residue 1068 and its downstream signaling proteins AKT and ERK in NCI-H1975 cells (EGFRL858R/T790M) even at low dosage (0.1-1 nM). Additionally, ASK120067 inhibits p-EGFR and p-Akt and p-erk in EGFR WT A431 cell until the concentration reaches 10 to 100 nM[1]. ASK120067 (oral gavage; 5-20 mg/kg; once daily; 21 days) results in significantly regressed tumor growth, with a tumor growth inhibition (TGI) rate of 85.7%, and administration of 10 mg/kg ASK120067 causes dramatic tumor shrinkage with a TGI rate of 99.3%, exhibiting a similar potency with Osimertinib[1]. [1]. Tao Zhang, et al. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance. Mol Cancer. 2020 May 13;19(1):90.

USP8-IN-1 is an inhibitor of USP8 with an IC 50 of 1.9 μM. USP8-IN-1 inhibits H1975 cell growth with a GI 50 of 82.04 μM [1].

Mobocertinib (tak788) is a potent inhibitor of epidermal growth factor receptor (EGFR) and an antineoplastic agent

PF-6274484, a high affinity, irreversible covalent inhibitor of EGFR kinase with Ki of 0.14 nM, inhibits the autophosphorylation of wild-type EGFR in A549 cells and EGFRL858R/T790M in H1975 cells with IC50 of 5.8 nM and 6.6 nM, respectively.

Cys-McMMAF, the active compound liberated from AlMcMMAF—a humanized anti-5T4 A1 antibody connected to the microtubule-disrupting molecule MMAF through a maleimidocaproyl linker—demonstrates antitumor effectiveness in two mouse tumor models (H1975 and MDA-MB-361-DYT2) [1].

EGFR-IN-1 TFA is an orally active and irreversible L858R/T790M mutant selective EGFR inhibitor. EGFR-IN-1 TFA potently inhibits Gefitinib-resistant EGFR L858R, T790M with 100-fold selectivity over wild-type EGFR . EGFR-IN-1 TFA displays strong antiproliferative activity against the H1975 cells and the first line mutant HCC827 cells. Antitumor activity [1] .

D561-0775 is a direct AMPK agonist, showing potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells.

E3330 is a potent and selective APE1(Ref-1) inhibitor, which suppressed NF-kappa B DNA-binding activity.

BAZ1A-IN-1 is a potent BAZ1A inhibitor with the KD value of 0.52 μM for the BAZ1A bromodomain. BAZ1A-IN-1 shows good anti-survival activity against cancer cell lines with high BAZ1A expression, but weak or no activity against cancer cells with low BAZ1A expression.

EGFR-IN-1, an orally active and irreversible selective inhibitor targeting L858R/T790M mutant EGFR, exhibits strong antiproliferative and antitumor activity, particularly against H1975 cells and first line mutant HCC827 cells. This compound potently inhibits Gefitinib-resistant EGFR L858R/T790M mutations with a 100-fold selectivity over the wild-type EGFR.