Abstract 4975: A small molecule pan Id protein antagonist shows strong antitumor activity

e14102 Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major signaling pathways involved in tumorigenesis. Components of these two pathways are frequently mutated in a broad range of tumors. ASN003 is a novel and highly selective small-molecule inhibitor of the RAS-RAF-MEK and PI3K pathways. Methods: The activity of ASN003 was determined using PI3K and BRAF enzymes, and efficacy was studied in human tumor xenograft models in mice. ASN003 is currently being investigated in patients with solid tumors in a Phase 1 trial using an accelerated dose titration design. In Part A, safety and tolerability of ASN003 is being studied in patients with advanced solid tumors. In Part B, safety, tolerability and preliminary efficacy of ASN003 will be evaluated in melanoma, CRC and NSCLC patients with a BRAF, PIK3CA or PTEN mutation. Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: ASN003 showed potent and highly selective inhibition of BRAF and PI3K-α and -δ, and low affinity for PI3K-ß. ASN003 showed strong antiproliferative activity in cell lines and caused significant tumor growth inhibition in xenograft models harboring BRAF and PIK3CA or PTEN mutations. ASN003 showed antiproliferative activity in B-RAF and MEK inhibitor resistant cell lines. ASN003 had a strong antitumor activity in a BRAFV600mutant melanoma PDX model resistant to BRAF inhibitors, vemurafenib and dabrafenib. In humans, to date, ASN003 was well tolerated at 10 and 20 mg QD. Adverse events were mild and peak plasma level of 120 nM at 10 mg QD was achieved with a half-life of > 12 h. Dose escalation is ongoing. Conclusions: ASN003 is a unique small molecule, with highly selective and potent inhibition of BRAF, PI3-α and -δ kinases. ASN003 has strong antitumor activity in various xenograft tumor models harboring both BRAF and PIK3CA/PTEN mutations, and in a BRAF inhibitor resistant melanoma PDX model. To date, ASN003 was well tolerated and achieved good systemic exposure. Updated and detailed clinical, PK and PD results will be presented. Clinical trial information: NCT02961283.

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A novel small-molecule fatty acid synthase inhibitor with antitumor activity by cell cycle arrest and cell division inhibition

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113407 ◽

2021 ◽

pp. 113407

Author(s):

Hongyan Qu ◽

Kai Shan ◽

Chunlei Tang ◽

Guozhen Cui ◽

Guoling Fu ◽

...

Keyword(s):

Cell Cycle ◽

Fatty Acid ◽

Cell Division ◽

Antitumor Activity ◽

Cell Cycle Arrest ◽

Small Molecule ◽

Fatty Acid Synthase ◽

Cycle Arrest ◽

Synthase Inhibitor ◽

Cell Division Inhibition

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Sulfated and Sulfur-Containing Steroids and Their Pharmacological Profile

Marine Drugs ◽

10.3390/md19050240 ◽

2021 ◽

Vol 19 (5) ◽

pp. 240

Author(s):

Tatyana A. Pounina ◽

Tatyana A. Gloriozova ◽

Nick Savidov ◽

Valery M. Dembitsky

Keyword(s):

Antitumor Activity ◽

Confidence Level ◽

Biological Activities ◽

Marine Sponges ◽

Bioactive Lipids ◽

Pharmacological Profile ◽

Wide Range ◽

Sulfated Steroids ◽

Strong Antitumor Activity ◽

Sulfur Containing

The review focuses on sulfated steroids that have been isolated from seaweeds, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. Sulfur-containing steroids and triterpenoids are sourced from sedentary marine coelenterates, plants, marine sediments, crude oil, and other geological deposits. The review presents the pharmacological profile of sulfated steroids, sulfur-containing steroids, and triterpenoids, which is based on data obtained using the PASS program. In addition, several semi-synthetic and synthetic epithio steroids, which represent a rare group of bioactive lipids that have not yet been found in nature, but possess a high level of antitumor activity, were included in this review for the comparative pharmacological characterization of this class of compounds. About 140 steroids and triterpenoids are presented in this review, which demonstrate a wide range of biological activities. Therefore, out of 71 sulfated steroids, thirteen show strong antitumor activity with a confidence level of more than 90%, out of 50 sulfur-containing steroids, only four show strong antitumor activity with a confidence level of more than 93%, and out of eighteen epithio steroids, thirteen steroids show strong antitumor activity with a confidence level of 91% to 97.4%.

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A Novel Chemical Attack on Notch-mediated transcription by targeting the NACK ATPase

10.21203/rs.3.rs-733100/v1 ◽

2021 ◽

Author(s):

G. Diluvio ◽

T. T. Kelley ◽

M. Lahiry ◽

A. Alvarez Trotta ◽

E. M. Kolb ◽

...

Keyword(s):

Antitumor Activity ◽

Mouse Models ◽

Small Molecule ◽

Ternary Complex ◽

Small Molecule Inhibitor ◽

Chemical Attack ◽

Dependent Function ◽

Molecule Inhibitor ◽

Efficacious Treatment ◽

Notch Activation

Abstract Notch Activation Complex Kinase, NACK, is a component of the Notch transcriptional machinery critical to Notch-mediated tumorigenesis. However, the mechanism by which NACK regulates the Notch-mediated transcription is not well understood. Here we demonstrate that NACK binds and hydrolyses ATP and that only ATP-bound NACK is able to bind to the Notch Ternary Complex (NTC). Considering this we sought to identify inhibitors of this ATP-Dependent function and, using computational pipelines, discovered the first small molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antitumor activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for efficacious treatment of Notch-driven cancers by blocking the Notch downstream NTC activity.

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