Last update 21 Nov 2024

KF-1601

Last update 21 Nov 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide dihydrochloride

+ [1]

Target

ABL1 x Bcr-Abl T315I x FLT3

Mechanism

ABL1 inhibitors(ABL proto-oncogene 1 inhibitors), Bcr-Abl T315I inhibitors(BCR-ABL T315I mutation inhibitors), FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Philadelphia chromosome positive chronic myelogenous leukemia

Inactive Indication-

Originator Organization

Immunoforge Co. Ltd.Startup

Active Organization

Immunoforge Co. Ltd.Startup

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

RegulationOrphan Drug (US)

100 Clinical Results associated with KF-1601

100 Translational Medicine associated with KF-1601

100 Patents (Medical) associated with KF-1601

Literatures (Medical) associated with KF-1601

03 Oct 2023·Medical oncology (Northwood, London, England)

Identification by molecular dynamic simulation and in vitro validation of SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl) oxy], as an inhibitor of the Abl^T315I mutant kinase to combat imatinib resistance in chronic myeloid leukemia.

Article

Author: Makkawi, Mohammed ; Abohassan, Mohammad ; Alasmari, Sultan ; Gahtani, Reem M ; Al Shahrani, Mesfer

The discovery of imatinib, a specific inhibitor of Abl kinase, revolutionized the therapeutic approach to chronic myeloid leukemia (CML); however, its efficacy can be impeded by the emergence of novel mutations within the kinase domain, particularly Abl^T315I, that lead to the development of drug resistance. It therefore remains necessary to identify specific inhibitors that can effectively target imatinib-resistant CML harboring the Abl^T315I mutation. A natural product library sourced from the ZINC database was screened against the experimental structure of Abl^T315I kinase to identify compounds that selectively target the mutated kinase. The top-scoring compound was empirically tested for inhibition of Abl^T315I kinase using a luminescence-based kit and for impact on cellular proliferation using the BaF3-BCR-ABL-T315I stable cell line. Computational docking and molecular dynamic simulations identified the compound SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl)oxy] acetamide, to effectively bind the catalytic domain of the mutant Abl^T315I kinase. Moreover, SISB-A1 exhibited greater preference than imatinib for amino acid residues of the mutant kinase's active site, including isoleucine 315. MMPBSA-based Gibbs binding free energy estimation predicted SISB-A1 to have a free energy of -51.5 versus -65.0 kcal/mol for the conventional Abl^T315I inhibitor ponatinib. Cell proliferation assays showed SISB-A1 to have a GI₅₀ of 164.0 nM against the ABL-T315I stable cell line, whereas imatinib had a GI₅₀ of 5035 nM. The IC₅₀ value obtained for SISB-A1 against the Abl^T315I kinase was 197.9 nM. The results indicate SISB-A1 to have a notable ability to bind the catalytic domain of the Abl^T315I mutant kinase and effectively suppress its activity, thereby surpassing the associated resistance to imatinib. Continued advancement of this lead compound has the potential to yield innovative therapeutics for imatinib-resistant CML.

01 Aug 2023·Chemico-biological interactions

A PKM2 inhibitor induces apoptosis and autophagy through JAK2 in human oral squamous cell carcinoma cells.

Article

Author: Gopula, Balraj ; Hu, Jing-Lan ; Weng, Jing-Ru ; Feng, Chia-Hsien ; Chu, Po-Chen

The enzyme pyruvate kinase M2 (PKM2) is involved in glycolysis, which plays an important role in the regulation of tumor progression. In this study, we investigated the anti-tumor activity of N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide (MTP), a PKM2 inhibitor, in oral squamous cell carcinoma (OSCC) cells. Our results showed that MTP inhibited cell growth with IC50 values of 0.59 μM and 0.78 μM in SCC2095 and HSC-3 OSCC cells, respectively. MTP induced caspase-dependent apoptosis, which was associated with the modulation of PKM2 and oncogenic biomarkers epidermal growth factor receptor and β-catenin. In addition, MTP increased the generation of reactive oxygen species (ROS) and modulated the expression of autophagic gene products, including LC3B-II and p62. Western blotting showed that MTP inhibited Janus kinase 2 (JAK2) signaling, and JAK2 overexpression partially reversed MTP-mediated cytotoxicity. Taken together, these data indicate the potential use of MTP as a therapeutic agent for OSCC.

01 Apr 2023·Bioorganic & Medicinal Chemistry Letters

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor

Article

Author: Lee, Jungwoo ; Han, Cheolkyu ; Jeong, Hee-Jin ; Lee, Jinwoo ; Kim, Sunjoo ; Yoon, Cheolhwan ; Jeon, Seeun ; Seo, Jeongbeob ; Kang, Hong-Jun ; Shin, Youngdo ; Yun, Jaesook ; Kang, Byung-Nam

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d₃)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC₅₀ = >10 μM) and showed potent inhibitory effects in cellular assay (IC₅₀ = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

100 Deals associated with KF-1601

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Philadelphia chromosome positive chronic myelogenous leukemia	Preclinical	KR	Immunoforge Co. Ltd.Startup	-

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KF-1601

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Translational Medicine

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