Aurora A inhibitors(Serine/threonine-protein kinase Aurora-A inhibitors), CSF-1R antagonists(Colony stimulating factor 1 receptor antagonists), FGFRs antagonists(Fibroblast growth factor receptors antagonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [6]

Active Indication-

Inactive Indication

Advanced cancerAdvanced Hepatocellular CarcinomaFallopian Tube Carcinoma+ [7]

Originator Organization

CASI Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

CASI Pharmaceuticals, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC25H31N7O6

InChIKeyKGWWHPZQLVVAPT-STTJLUEPSA-N

CAS Registry1453868-32-0

Clinical Trials associated with ENMD-2076

NCT02234986 / CompletedPhase 2

A Phase 2, Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients With Advanced Fibrolamellar Carcinoma (FLC)

The purpose of the study is to determine whether once-daily dosing with ENMD-2076 will be a safe and effective treatment in patients with FLC. Safety will be measured by looking at the adverse events that may happen and the efficacy will look at the progression of the disease over time.

Start Date01 Oct 2015

Sponsor / Collaborator

CASI Pharmaceuticals, Inc.

CTR20150075 / RecruitingNot Applicable

一项ENMD-2076治疗局部复发或转移的三阴性乳腺癌晚期患者的安全性和耐受性的IIa期临床试验

[Translation] A Phase IIa clinical trial to evaluate the safety and tolerability of ENMD-2076 in patients with locally recurrent or metastatic advanced triple-negative breast cancer

主要目的：通过三阴性乳腺癌受试者口服一定剂量的ENMD-2076，观察不良事件（AEs）发生的频率和严重程度，评估ENMD-2076的安全性和耐受性，在中国患者人群中确定合适剂量, 进而确定Ⅱb期临床试验治疗剂量。次要目的: 观察肿瘤变化和疾病进展，评价治疗的临床受益率。通过对肿瘤组织标本和血液样品进行基因外显子全序列的分析，评价其与ENMD-2076的药效相关性。

[Translation]

Primary purpose: To observe the frequency and severity of adverse events (AEs) by oral administration of a certain dose of ENMD-2076 to subjects with triple-negative breast cancer, evaluate the safety and tolerability of ENMD-2076, determine the appropriate dose in the Chinese patient population, and then determine the treatment dose for the Phase IIb clinical trial. Secondary purpose: To observe tumor changes and disease progression and evaluate the clinical benefit rate of treatment. By analyzing the full sequence of gene exons in tumor tissue specimens and blood samples, evaluate their correlation with the efficacy of ENMD-2076.

Start Date24 Mar 2015

Sponsor / Collaborator

Alcami Carolinas Corp.

[+2]

NCT01914510 / CompletedPhase 2IIT

Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas

This is a phase 2 study to see how useful, safe, and tolerable an investigational drug called ENMD-2076 is in treating patients with ovarian clear cell carcinomas.
ENMD-2076 is an oral drug that works by blocking certain enzymes called Aurora A and tyrosine kinase from working. These enzymes are needed for cells to divide including cancer cells. ENMD-2076 also works by stopping the growth of new blood vessels which would provide the tumor with nutrients for it to grow. It is believed that by blocking Aurora A and tyrosine kinase enzymes from working and stopping new blood vessels from growing, the tumors may stop growing or shrink.

Start Date01 Sep 2013

Sponsor / Collaborator

University Health Network

100 Clinical Results associated with ENMD-2076

100 Translational Medicine associated with ENMD-2076

100 Patents (Medical) associated with ENMD-2076

Literatures (Medical) associated with ENMD-2076

01 Aug 2023·European journal of medicinal chemistry

Discovery of a first-in-class Aurora A covalent inhibitor for the treatment of triple negative breast cancer

Article

Author: Zhu, Chengchen ; Lu, Gui ; Chan, Albert S C ; Zhang, Bin

Aurora kinases, which belong to the serine/threonine protein family, play critical roles in the regulation of the cell cycle and mitotic spindle assembly. They are frequently highly expressed in various types of tumors, and the use of selective Aurora kinase inhibitors has become a potential treatment option for cancer therapy. Despite the development of some reversible Aurora kinase inhibitors, none has been approved for clinical use yet. In this study, we report the discovery of the first-in-class irreversible Aurora A covalent inhibitors that target a cysteine residue at the substrate binding site. These inhibitors were characterized in enzymatic and cellular assays, and 11c exhibited selective inhibition to normal and cancer cells, as well as to Aurora A and B kinases. The covalent binding of 11c to Aurora A was confirmed by SPR, MS, and enzyme kinetic analysis, and Cys290-mediated covalent inhibition was supported through a bottom-up analysis of inhibitor-modified targets. Moreover, Western blotting assays were conducted on cells and tissues, and cellular thermal shift assays (CETSA) were further performed on cells to demonstrate the selectivity to Aurora A kinase. 11c displayed comparable therapeutic efficacy in an MDA-MB-231 xenograft mouse model relative to the positive control ENMD-2076, while requiring only half the dose of ENMD-2076. These results confirmed that 11c may be a promising drug candidate for the treatment of triple negative breast cancer (TNBC). Our work may provide a new perspective on the design of covalent inhibitors of Aurora kinase.

01 Oct 2022·Clinical Lymphoma Myeloma & Leukemia

AML-377 A “Designed” High-Throughput Drug Screening Strategy Identifies Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML

Article

Author: Neuenschwander, Martin ; Martelli, Maria Paola ; Pierangeli, Sara ; Sabino, Marcella ; Ferrari, Alessio ; Donnini, Serena ; Tini, Valentina ; Silvestri, Serenella ; Mezzasoma, Federica ; Ranieri, Roberta ; Kries, Jens Peter von ; Falini, Brunangelo ; Spinozzi, Giulio ; Gionfriddo, Ilaria ; Kleissle, Sabrina ; Milano, Francesca

CONTEXT:

Nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML) accounts for one-third of adult AML and displays distinctive biological and clinical features. Despite its chemo-sensitivity and a relatively favorable prognosis, this leukemia lacks any specific therapies. Because NPM1 mutant protein is not druggable, targeting its non-oncogene addictions and its specific vulnerabilities can represent an alternative option for identifying a tailored therapy for NPM1-mutated AML.

OBJECTIVE:

We performed a high-throughput screening (HTS) of different chemical compounds and drug libraries to find drugs or compounds 'synthetically lethal' with NPM1 mutation and/or showing more selective activity in AML with NPM1 mutation.

METHODS:

In collaboration with the Screening Unit of Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP; (Berlin, Germany), we performed an HTS of 38720 drugs/compounds in a 384-well format. The assay readout was cellular metabolism/viability by CellTiter Blue assay at 48 hours. The screening was properly designed in 2 steps to increase efficiency, exclude compounds with general toxicity, and identify compounds ('hits') selectively active against the only two available NPM1-mutated AML cell lines, OCI-AML3 and IMS-M2, but not against wild-type controls.

RESULTS:

Sixty-two hit compounds that met qHTS threshold criteria were rescreened in a dose-response experiment. From this analysis, we obtained 37 compounds able to selectively kill IMS-M2 (IMS-M2 %viability <50 vs. OCI-AML2 %viability >75). We focused on Aurora kinase A inhibitors (AURKAi) because 4 of the selective compounds were directed against this kinase. In the validation assay, 2 compounds (MK-5108 and MK-8745) were confirmed as more active against NPM1-mutated than NPM1-wild-type AML cells by either CyQUANT or apoptosis assay. Strikingly, we confirmed selectivity for two additional AURKAi (Alisertib and ENMD-2076, both isoform-selective inhibitors of AURKA) that were not included in the screening library. The AURKAi were also effective in reducing tumor burden in NPM1-mutated PDX cell models and provided a survival advantage compared with vehicle-treated mice (60 vs. 32 days, P=0.005).

CONCLUSIONS:

We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identification of promising lead compounds. Our study is the first to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML.

01 Dec 2020·The oncologistQ2 · MEDICINE

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma

Q2 · MEDICINE

Article

Author: O'Neill, Allison F. ; Ren, Ken ; Kingham, Peter T. ; Kobos, Rachel ; Beg, Muhammad S. ; Venook, Alan P. ; Leong, Stephen ; Hoti, Emir ; Yopp, Adam ; Bradley, Mikaela ; Brennan, Cameron ; Mayer, Robert ; Abou-Alfa, Ghassan K. ; Ly, Michele ; Crown, John ; Gordan, John D. ; Valentino, Emily ; LaQuaglia, Michael ; Leonard, Gregory ; Zukiwski, Alexander ; Harding, James J. ; Markowitz, David ; Basturk, Olca

Abstract:

Lessons Learned:

The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components.

Background:

Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor.

Methods:

Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0–2 or Lansky 70–100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study.

Results:

Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study—two due to disease progression and one due to pulmonary embolism not related to ENMD-2076.

Conclusion:

The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

News (Medical) associated with ENMD-2076

05 Feb 2010

·www.biospace.com

EntreMed, Inc. Raises Additional $2.5 Million In Registered Direct Offering

ROCKVILLE, Md., Feb. 4 /PRNewswire-FirstCall/ -- EntreMed, Inc. today announced that it completed a registered direct offering of 3,846,154 shares of its common stock, at a purchase price of $0.65 per share, to a single accredited institutional investor. The sale resulted in gross proceeds to the Company of $2.5 million. The terms of the purchase were set forth in a stock purchase agreement entered into by the parties on February 3, 2010. The per share purchase price reflects a 10% discount to the five-day average closing sale price ending on February 2, 2010. EntreMed plans to use the net proceeds of the offering, which are expected to be approximately $2.3 million after deducting the placement agent's fee and estimated offering expenses payable by EntreMed, to further clinical development of its Aurora A/angiogenic kinase inhibitor, ENMD-2076, and for other general corporate purposes. This press release does not and shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities, nor shall there be any sale of the securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any state. About EntreMed EntreMed, Inc. is a clinical-stage pharmaceutical company committed to developing primarily ENMD-2076, a selective angiogenic kinase inhibitor, for the treatment of cancer. ENMD-2076 is currently in Phase 1 studies in advanced cancers, multiple myeloma, and leukemia. The Company's other therapeutic candidates include MKC-1, an oral cell-cycle regulator with activity against the mTOR pathway currently in multiple Phase 2 clinical trials for cancer, and ENMD-1198, a novel antimitotic agent currently in Phase 1 studies in advanced cancers. The Company also has an approved IND application for Panzem(R) in rheumatoid arthritis. Additional information about EntreMed is available on the Company's web site at and in various filings with the Securities and Exchange Commission. CONTACT: Ginny Dunn, Associate Director, Corporate Communications & Investor Relations of EntreMed, Inc., +1-240-864-2643 Web site:

16 Oct 2007

·www.biospace.com

EntreMed, Inc. Appoints Senior Vice President of Research and Development Dr. Kenneth W. Bair Joins Senior Management Team

ROCKVILLE, Md., Oct. 16 /PRNewswire-FirstCall/ -- EntreMed, Inc. , a clinical-stage pharmaceutical company developing therapeutics for the treatment of cancer and inflammatory diseases, today announced that Kenneth W. Bair, Ph.D. has been appointed its Senior Vice President, Research and Development. Dr. Bair has also been elected an executive officer of EntreMed by the Board of Directors, reporting to James S. Burns, President & CEO. (Logo: ) Dr. Bair brings to EntreMed over 25 years of management experience in oncology drug discovery, development and chemistry. Prior to joining EntreMed, Dr. Bair served as Senior Vice President and Head, BioPharmaceuticals Research at Chiron Corporation in Emeryville, California. Prior to joining Chiron Corporation in 2003, Dr. Bair was Vice President, Discovery Oncology at Pharmacia Corporation in Peapack, New Jersey. From 1982 until joining Pharmacia, Dr. Bair held positions of increasing responsibility within the pharmaceutical industry, including Unit Head of Oncology at Novartis Pharmaceuticals Corporation and Executive Director and Head, Oncology Research Program, Sandoz Pharmaceuticals Corporation; and various oncology research positions at Burroughs Wellcome, Research Triangle Park, North Carolina. Dr. Bair received his Ph.D. in organic chemistry from Brandeis University, Waltham, Massachusetts, and was a Postdoctoral Fellow at the Massachusetts Institute of Technology, Cambridge, Massachusetts. Dr. Bair commented on his appointment at EntreMed, "I am delighted to be joining the EntreMed team. The Company has extensive scientific expertise in angiogenesis, cell cycle regulation, kinase inhibition and inflammation, which provide a strong foundation for building a leading oncology franchise. EntreMed's pipeline of HIF-1 alpha and kinase inhibitors fit well with my background and research interests. I look forward to leading the advancement of EntreMed's mechanism-based drugs for the treatment of cancer and inflammatory diseases." James S. Burns, EntreMed President & CEO commented, "I am very pleased to welcome Ken to EntreMed's leadership team. Ken joins EntreMed with a strong oncology research and development background in large pharmaceutical and biotech companies, experience that will be instrumental in leading EntreMed into its next phase of development." Mr. Burns continued, "Ken has a solid track record in identifying and developing oncology compounds. As Senior Vice President of Research and Development, Ken will play a critical role in leading the development of our ongoing research programs, prioritizing the existing portfolio, and identifying new compounds for our pipeline in order to select the best programs based on the strength of the data and their prospective competitive position." About EntreMed EntreMed, Inc. is a clinical-stage pharmaceutical company developing therapeutic candidates primarily for the treatment of cancer and inflammation. Panzem(R) NCD (2-methoxyestradiol or 2ME2) is currently in multiple Phase 2 clinical trials for cancer. MKC-1, an oral cell-cycle regulator, is in multiple Phase 1 and 2 studies for cancer. ENMD-1198, a novel tubulin-binding agent, is in Phase 1 studies in advanced cancers. Panzem(R) is also in preclinical development for rheumatoid arthritis, and ENMD-2076, a dual-acting Aurora-angiogenesis inhibitor, is in preclinical development for cancer. EntreMed's goal is to develop and commercialize new compounds based on the Company's expertise in angiogenesis, cell-cycle regulation and inflammation - processes vital to the treatment of cancer and other diseases, such as rheumatoid arthritis. Additional information about EntreMed is available on the Company's web site at and in various filings with the Securities and Exchange Commission. Forward Looking Statements This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act with respect to the outlook for expectations for future financial or business performance (including the timing of royalty revenues and future R&D expenditures), strategies, expectations and goals. Forward-looking statements are subject to numerous assumptions, risks and uncertainties, which change over time. Forward-looking statements speak only as of the date they are made, and no duty to update forward-looking statements is assumed. Actual results could differ materially from those currently anticipated due to a number of factors, including those set forth in Securities and Exchange Commission filings under "Risk Factors," including risks relating to the need for additional capital and the uncertainty of additional funding; variations in actual sales of Thalomid(R), risks associated with the Company's product candidates; the early-stage products under development; results in preclinical models are not necessarily indicative of clinical results, uncertainties relating to preclinical and clinical trials; success in the clinical development of any products; dependence on third parties; future capital needs; and risks relating to the commercialization, if any, of the Company's proposed products (such as marketing, safety, regulatory, patent, product liability, supply, competition and other risks). CONTACT: Ginny Dunn, Associate Director, Corporate Communications & Investor Relations of EntreMed, Inc., +1-240-864-2643 Web site:

100 Deals associated with ENMD-2076

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Hepatocellular Carcinoma	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Oct 2015
Fibrolamellar Hepatocellular Carcinoma	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Oct 2015
Triple Negative Breast Cancer	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Jul 2012
Triple Negative Breast Cancer	Phase 2	CN	CASI Pharmaceuticals, Inc.	01 Jul 2012
Fallopian Tube Carcinoma	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Apr 2010
Fallopian Tube Carcinoma	Phase 2	CA	CASI Pharmaceuticals, Inc.	01 Apr 2010
Peritoneal Neoplasms	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Apr 2010
Peritoneal Neoplasms	Phase 2	CA	CASI Pharmaceuticals, Inc.	01 Apr 2010
Platinum-Resistant Ovarian Carcinoma	Phase 2	US	CASI Pharmaceuticals, Inc.	01 Apr 2010
Platinum-Resistant Ovarian Carcinoma	Phase 2	CA	CASI Pharmaceuticals, Inc.	01 Apr 2010

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Pubmed \| Oncologist	Phase 2	Fibrolamellar Hepatocellular Carcinoma DNAJB1-PRKACA gene fusion transcript RNA \| Aurora kinase A	35	ENMD-2076	kpnifsoofz(iqugqdfsht) = errgrnkuqb wymgiqeknt (laxxzarzaw ) View more	Negative	01 Dec 2020
NCT01914510 (CTgov)	Phase 2	Ovarian clear cell adenocarcinoma	40	ENMD-2076	yxtqqtdwmb(qmuqexrdka) = dckgbbqfwv lipwvrawfy (atimgqynms, kfjgivgkap - zelgzphzvu) View more	-	13 Dec 2019
NCT01719744 (Pubmed \| Sci Rep) Manual	Phase 2	Locally Advanced Soft Tissue Sarcoma First line PTPRB Mutation	25	ENMD-2076	tfizddxrhf(jmyyvhvycc) = atcddxnrio beqetaxjkp (ponpyqllyo, 3.2 - 38.4) View more	Negative	14 May 2019
NCT01639248 (Pubmed \| Clin Cancer Res \| Breast Cancer Res) Manual	Phase 2	Triple Negative Breast Cancer Second line triple-negative	41	ENMD-2076	lkpnfcucpv(mctleaxclk) = crnwizdrqo rzxlygxlze (ynmsvqmdmv, 6 - 32.8)	Positive	02 Aug 2018
NCT01719744 (CTgov)	Phase 2	Metastatic Soft Tissue Sarcoma	25	ENMD-2076	isrltestxj(kslmljfvwy) = gcwycoaszf shdclyfwsk (afibxhlkkp, frcacopuvb - hzszovhxrb) View more	-	07 Nov 2017
NCT01914510 (ASCO2017)	Phase 2	Ovarian clear cell carcinoma	40	ENMD-2076	nwulwjommh(mhwhzelizh) = sefaezuukm tuwnzhvzoc (gezpilqmks, 3.4 - 4.4)	-	30 May 2017
Pubmed \| Invest New Drugs Manual	Phase 1	Acute Myeloid Leukemia \| Chronic Myelomonocytic Leukemia	27	ENMD-2076	ddectmkccz(jjiurslrtw) = 225 mg orally once daily uaqdrkkpyo (kostrlnsrk ) View more	Positive	01 Oct 2016
NCT01914510 (ASCO2016)	Phase 2	Recurrent Ovarian Clear Cell Adenocarcinoma	32	ENMD-2076 275 mg	kauldinsqf(fyqeacacgv) = Drug-related adverse events (AEs) occurred in 24/28 (86%) evaluable pts, the most common being Grade (Gr) 1/2 fatigue, nausea/vomiting, hypertension and diarrhea. Gr ≥ 3 AEs were reported in 46% of pts. AE resulted in dose reductions in 11 pts (39%) and led to treatment discontinuation in 3. ptdwcxrmkc (wspwwvslji )	Positive	20 May 2016
NCT01719744 (ASCO2014)	Phase 2	Locally Advanced Soft Tissue Sarcoma First line	10	ENMD-2076	yrhxszwgat(qukqambzhm) = 1 pt developed PRES presenting as grade 4 loss of consciousness at Cycle 1 Day 15 required ICU admission. Full neurological recovery was attained after cessation of treatment atnflwxhuh (oszcxxsfti ) View more	-	20 May 2014
ASCO2011	Phase 2	Platinum-Resistant Ovarian Carcinoma	64	ENMD-2076	obemaynvsp(qsnmkwviae) = jooquoijkz uecmooxlrb (vlsotuhxxn )	-	20 May 2011

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