Delving into the Latest Updates on Filanesib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Filanesib (USAN/INN), Filanesib-hydrochloride

Target

KIF11

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [2]

Active Indication-

Inactive Indication

Acute Myeloid LeukemiaAdvanced cancerAdvanced Malignant Solid Neoplasm+ [5]

Originator Organization

Array BioPharma, Inc.

Active Organization-

Inactive Organization

Array BioPharma, Inc.

Pfizer Inc.

Celgene Corp.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC20H22F2N4O2S

InChIKeyLLXISKGBWFTGEI-FQEVSTJZSA-N

CAS Registry885060-09-3

BACKGROUNDCancer-associated fibroblasts (CAFs) play a crucial role in tumor microenvironment regulation and cancer progression. This study assessed the significance and predictive potential of CAFs in breast cancer prognosis.METHODSThe study included 1503 breast cancer patients. Cancer-associated fibroblasts were identified using morphologic features from hematoxylin and eosin slides. The study analyzed clinicopathologic parameters, survival rates, immune cells, gene sets, and prognostic models using gene-set enrichment analysis, in silico cytometry, pathway analysis, in vitro drug-screening, and gradient-boosting machine (GBM)-learning.RESULTSThe presence of CAFs correlated significantly with young age, lymphatic invasion, and perineural invasion. In silico cytometry showed altered leukocyte subsets in the presence of CAFs, with decreased CD8+ T cells. Gene-set enrichment analysis showed associations with critical processes such as the epithelial-mesenchymal transition and immune modulation. Drug sensitivity analysis in breast cancer cell lines with varying fibroblast activation protein-α expression suggested that CAF-targeted therapies might enhance the efficacy of certain anticancer drugs including ARRY-520, ispinesib-mesylate, paclitaxel, and docetaxel. Integrating CAF presence with machine-learning improved survival prediction. For breast cancer patients, CAFs were independent prognostic markers for worse disease-specific survival and disease-free survival.CONCLUSIONThis study highlighted the significance of CAFs in breast cancer biology and provided compelling evidence of their impact on patient outcomes and treatment response. The findings offer valuable insights into the potential of CAFs as prognostic and predictive biomarkers and support the development of CAF-targeted therapies to improve breast cancer management.

01 Aug 2022·Anti-Cancer Agents in Medicinal ChemistryQ4 · MEDICINE

Role of KSP Inhibitors as Anti-Cancer Therapeutics: An Update

Q4 · MEDICINE

Review

Author: Suvarna, Vasanti ; Chamariya, Rinkal

Abstract:Regardless of the growing discovery of anticancer treatments targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance because tumours harbor a greater population of actively dividing cells than normal tissues. Conventional anti-mitotic agents or microtubule poisons acting on the major mitotic spindle protein tubulin have been effectively used in clinical settings for cancer chemotherapy over the last three decades. However, the use of these drugs is associated with limited clinical utility due to serious side effects such as debilitating and dose-limiting peripheral neuropathy, myelosuppression, drug resistance, and allergic reactions. Therefore, research initiatives have been undertaken to develop novel microtubule motor proteins inhibitors that can potentially circumvent the limitations associated with conventional microtubule poisons. Kinesin spindle proteins (KSP) belonging to the kinesin-5 family play a crucial role during mitosis and unregulated cell proliferation. Evidence from preclinical studies and different phases of clinical trials have presented kinesin spindle protein as a promising target for cancer therapeutics. Kinesin spindle protein inhibitors causing mitosis disruption without interfering with microtubule dynamics in non-dividing cells offer a potential therapeutic alternative for the management of several major cancer types and are devoid of side effects associated with classical anti-mitotic drugs. This review summarizes recent data highlighting progress in the discovery of targeted KSP inhibitors and presents the development of scaffolds, structure-activity relationships, and outcomes of biological and enzyme inhibition studies. We reviewed the recent literature reports published over the last decade, using various electronic database searches such as PubMed, Embase, Medline, Web of Science, and Google Scholar. Clinical trial data till 2021 was retrieved from ClinicalTrial.gov. Major chemical classes developed as selective KSP inhibitors include dihydropyrimidines, β-carbolines, carbazoles, benzimidazoles, fused aryl derivatives, pyrimidines, fused pyrimidines, quinazolines, quinolones, thiadiazolines, spiropyran, and azobenzenes. Drugs such as filanesib, litronesib, ispinesib have entered clinical trials; the most advanced phase explored is Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.

29 Mar 2022·ACS OmegaQ3 · CHEMISTRY

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach

Q3 · CHEMISTRY

ArticleOA

Author: Shukla, Manjari ; Erande, Rohan D. ; Chavan, Kailas A. ; Bhattacharyya, Sudipta ; Mali, Ghanshyam ; Maji, Sushobhan ; Chauhan, Amar Nath Singh

An ecofriendly, inexpensive, and efficient route for synthesizing 3,3'-bis(indolyl)methanes (BIMs) and their derivatives was carried out by an electrophilic substitution reaction of indole with structurally divergent aldehydes and ketones using taurine and water as a green catalyst and solvent, respectively, under sonication conditions. Using water as the only solvent, the catalytic process demonstrated outstanding activity, productivity, and broad functional group tolerance, affording the required BIM natural products and derivatives in excellent yields (59-90%). Furthermore, in silico based structure activity analysis of the synthesized BIM derivatives divulges their potential ability to bind antineoplastic drug target and spindle motor protein kinesin Eg5. The precise binding mode of BIM derivatives with the ATPase motor domain of Eg5 is structurally reminiscent with previously reported allosteric inhibitor Arry520, which is under phase III clinical trials. Nevertheless, detailed analysis of the binding poses indicates that BIM derivatives bind the allosteric pocket of the Eg5 motor domain more robustly than Arry520; moreover, unlike Arry520, BIM binding is found to be resistant to drug-resistant mutations of Eg5. Accordingly, a structure-guided mechanism of Eg5 inhibition by synthesized BIM derivatives is proposed.

100 Deals associated with Filanesib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11754	Filanesib	-	DB06040

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Phase 3	ES	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	GR	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	SE	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	BE	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	GB	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	GB	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	BE	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	SE	Array BioPharma, Inc.	-
Multiple Myeloma	Phase 3	ES	Array BioPharma, Inc.	-
Multiple Myeloma	Preclinical	GR	Array BioPharma, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01372540 (Pubmed) Manual	Phase 1	Relapse multiple myeloma Second line	63	Dexamethasone+filanesib+carfilzomib (Part A)	(ikbnhkeqyl) = Among 30 patients treated at the MTD for the Part A dose-expansion cohorts with filanesib 1.5 mg/m2, carfilzomib 20/27 mg/m2, and dexamethasone 4 mg,A total of 14 patients were treated at the MTD for the Part B dose-expansion cohort with filanesib 1.5 mg/m2, carfilzomib 20/56 mg/m2, and dexamethasone (4 mg prior to each carfilzomib dose in 10 patients and 40 mg on days 1, 8, and 15 in 4 patients due to protocol amendment) mzfupejvvc (nbrbyadurv ) View more	Positive	01 Oct 2019
				Dexamethasone+filanesib+carfilzomib (Part B)
NCT00821249 (Pubmed) Manual	Phase 1/2	Multiple Myeloma	-	Dexamethasone+Empegfilgrastim+Filanesib	(ynzavgzcld) = ucdcsuraih btsizznmbe (ubzhofuviu ) View more	Positive	01 Dec 2017
				Filanesib plus dexamethasone	-
NCT01989325 (EHA2015)	Phase 2	Relapse multiple myeloma	247	Filanesib (Patients with low AAG)	(czsgznmlzo) = jpjvynivio yrlmjobqtn (qgfmmmqcdl )	-	21 May 2015
				Filanesib (Patients with high AAG)	(czsgznmlzo) = ximqfzstuq yrlmjobqtn (qgfmmmqcdl )
NCT00462358 (Pubmed \| Invest New Drugs) Manual	Phase 1	Solid tumor	41	filanesib (Initial Schedules)	(lpgpntewtf) = vpujrsdapp gajgujezpr (gioumvsxbx )	Positive	01 Apr 2015
				filanesib (Alternate Schedules)	(lpgpntewtf) = ywlmcionxo gajgujezpr (gioumvsxbx )
NCT00637052 (Pubmed \| Cancer)	Phase 1	Refractory Leukemia KSP inhibition	36	ARRY-520	(rekudthgja) = nwmjgqjyte glzlmpimvy (rlldkzgjxt )	Negative	15 Jul 2012
ASCO2010	Phase 1	Solid tumor	34	ARRY-520	(xbuxbqsmic) = gamcmccjgq egrqmugqup (jfltyorszi ) View more	-	20 May 2010
ASCO2009	Phase 1	Leukemia	15	ARRY-520	(molcoqqdlp) = oxsylzeeju kolyqloqwd (lrbczixpko )	-	20 May 2009