Delving into the Latest Updates on Tasisulam Sodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Tasisulam, Tasisulam sodium (USAN), 他斯索兰

+ [6]

Target-

Mechanism

Apoptosis stimulants

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesDigestive System Disorders+ [6]

Active Indication-

Inactive Indication

Acute Myeloid LeukemiaAdvanced cancerAdvanced Malignant Solid Neoplasm+ [13]

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC11H6BrCl2NO3S2

InChIKeyWWONFUQGBVOKOF-UHFFFAOYSA-N

CAS Registry519055-62-0

View All Structures (2)

The purpose of this study is to evaluate whether tasisulam acts as an inducer of CYP3A using midazolam as a sensitive and specific probe substrate of CYP3A.
The study will also assess the safety and tolerability of tasisulam and midazolam given in combination and document any antitumor activity with tasisulam.

Start Date01 Sep 2010

Sponsor / Collaborator

Eli Lilly & Co.

NCT01185548 / TerminatedPhase 1

The Effect of Tasisulam on the CYP2C9-Mediated Metabolism of Tolbutamide: A Pharmacokinetic Interaction Study in Cancer Patients With Advanced and/or Metastatic Solid Tumors or Lymphoma

The purpose of this study was to assess the effect of tasisulam as an inhibitor of CYP2C9, using tolbutamide as a probe substrate. This study was to have 3 treatment periods, and continued access in an extension period. Period 1 is 4 days in length. Periods 2 and 3 are each approximately 28 days in length. Due to the early termination of the trial, only 1 Period 3 participant enrolled in the extension period before study termination.

Start Date01 Jul 2010

Sponsor / Collaborator

Eli Lilly & Co.

EUCTR2009-014591-21-GB / Not yet recruitingNot Applicable

A Randomized Phase 3 Study of Tasisulam Administered as an Intravenous Infusion on Day 1 of a 28-Day Cycle vs. Paclitaxel as Second-Line Treatment in Patients with Metastatic Melanoma

Start Date31 Mar 2010

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Tasisulam Sodium

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100 Translational Medicine associated with Tasisulam Sodium

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100 Patents (Medical) associated with Tasisulam Sodium

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18

Literatures (Medical) associated with Tasisulam Sodium

21 Oct 2022·Chemistry – A European Journal

Multistep Continuous Flow Synthesis of Isolable NH₂‐Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide

Article

Author: Andresini, Michael ; Luisi, Renzo ; Poisson, Jean‐François ; Ciriaco, Fulvio ; Carret, Sébastien ; Degennaro, Leonardo

AbstractThe growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza‐analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH2‐sulfinamidines by nucleophilic attack of organometallic reagents to in situ prepared N‐(trimethylsilyl)‐N‐trityl‐λ4‐sulfanediimine (Tr−N=S=N−TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen‐lithium exchange of aryl bromides and iodides with n‐butyllithium. Moreover, the synthetic potential of the methodology was assessed by exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.

01 Jan 2020·Nature Chemical Biology

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Article

Author: Zhang, Tinghu ; Donovan, Katherine A ; Yoon, Hojong ; Fischer, Eric S ; Li, Zhengnian ; Nowak, Radosław P ; Faust, Tyler B ; Cai, Quan ; Gray, Nathanael S ; Eleuteri, Nicholas A

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

01 Jun 2018·European Journal of Drug Metabolism and PharmacokineticsQ4 · MEDICINE

Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam

Q4 · MEDICINE

Article

Author: Chappell, Jill ; Kellie Turner, P ; Ng, Wee Teck ; Posada, Maria ; Twelves, Chris ; Perkins, Everett J

BACKGROUND AND OBJECTIVESCytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs). This paper describes the development and verification of SimCYP^®-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam.METHODSA PBPK model was optimized in SimCYP^® for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model.RESULTSThe optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3-6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7-5.4; measured mean AUC ratio = 5.7).CONCLUSIONSThis optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients.

100 Deals associated with Tasisulam Sodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D09389	-	-	DB11941

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic melanoma	Phase 3	IT	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	SE	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	TW	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	CA	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	GB	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	BE	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	AU	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	PL	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	FI	Eli Lilly & Co.	01 Dec 2009
Metastatic melanoma	Phase 3	KR	Eli Lilly & Co.	01 Dec 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01209832 (CTgov)	Phase 1	Advanced cancer \| Lymphoma	11	Midazolam (Midazolam)	qbdthpegeb(oacseefmtd) = ggmlznefrx fuiuidokdn (aeulwsnchc, wtmsbkjerb - yrfpigudcx) View more	-	18 Mar 2019
				Tasisulam+Midazolam (Midazolam + Tasisulam)	qbdthpegeb(oacseefmtd) = zobkqcnlga fuiuidokdn (aeulwsnchc, nfzntxhvxt - kfgsaxxjow) View more
NCT01185548 (JZAR, CTgov)	Phase 1	Metastatic Solid Tumor \| Advanced cancer \| Lymphoma	4	Tasisulam+Tolbutamide	svoblfmshl(djiibulflq) = iapgamiftj snnbwznjbv (amgjwfdeok, jtsvfrnsht - lifwtjwjtx) View more	-	19 Oct 2018
NCT00363766 (CTgov)	Phase 2	metastatic non-small cell lung cancer	52	LY573636 (LY573636 Target Cmax 420 µg/mL)	atsghqylns(ejactfibfd) = jqbrdkzobs kbwaboovae (bzhkbibhkf, tnofjivela - wfpgzkruju) View more	-	19 Oct 2018
				LY573636 (LY573636 Target Cmax 380 µg/mL)	atsghqylns(ejactfibfd) = olmtbkynrx kbwaboovae (bzhkbibhkf, bacrdiltjh - qwlwguepai) View more
NCT00718159 (CTgov)	Phase 1	Acute Myeloid Leukemia \| Thrombocythemia, Essential	23	LY573636-sodium	pdjhhvwmcp(skqtovldli) = tmeijyvucc gfwwwmtksg (eyvmjhdcbu, dubpacgrno - ajyjkyollq) View more	-	16 Oct 2018
NCT01214668 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	31	LY+Dox (LY 300 μg/mL + Dox)	(noknowwtan) = ugtdmaerbt plndrmpkbh (iytzpglwdw, mfjmpcnjau - kvnpkhxcee) View more	-	16 Oct 2018
				LY+Dox (LY 320 μg/mL + Dox)	(noknowwtan) = kbuvldbqzb plndrmpkbh (iytzpglwdw, hiqyeiwvqk - fhyzbhzrkv) View more
NCT00992225 (CTgov)	Phase 2	Metastatic breast cancer	43	LY573636-sodium	mljzinmhof(watfgfmemg) = fidevsgpxy bflyauzkxg (iowuanhjgj, jltfojirmh - kctrbizzvy) View more	-	17 Jul 2018
NCT01006252 (SUMMIT-1, CTgov)	Phase 3	Metastatic melanoma	336	Tasisulam-sodium (Tasisulam-sodium)	(zohfdtgmah) = vbzduqsour doaljnlsts (sqmqoqprvt, tjszucvdtf - fshbonlgnt) View more	-	17 Jul 2018
				Paclitaxel (Paclitaxel)	(zohfdtgmah) = lmhnqpjzhi doaljnlsts (sqmqoqprvt, sodkrfjtco - sfagyigvel) View more
NCT00383292 (CTgov)	Phase 2	Metastatic melanoma \| Unresectable Melanoma	130	tasisulam	klywhxbrgk(qldqmkcxcl) = qglihvbrmu qiphxkzqrv (jdhndgsnog, oqbgyvchip - uorrswdwam) View more	-	06 Jun 2018
NCT00490451 (CTgov)	Phase 2	Metastatic Soft Tissue Sarcoma	101	LY573636 (LY573636 Target Cmax 420 µg/mL)	ajhsrugges(taqbjryutn) = gfybujmjfj ysdktasrop (kwgqncrdgp, lggknjasml - odyqeblkoz) View more	-	02 May 2018
				LY573636 (LY573636 Target Cmax 360 µg/mL)	ajhsrugges(taqbjryutn) = awupczqhek ysdktasrop (kwgqncrdgp, igdjioxlcf - xwhlwmufjm) View more
NCT00428610 (CTgov)	Phase 2	Primary peritoneal carcinoma \| Platinum-Resistant Ovarian Carcinoma \| Fallopian Tube Carcinoma	103	LY573636 (Target Cmax 420 µg/mL)	fqvxnawgro(dnpztyvoyz) = rywhscnngr envcilfxeq (xttrjioouf, fvmlzioapm - braoaoyqks) View more	-	19 Apr 2018
				LY573636 (Target Cmax 360 μg/mL)	fqvxnawgro(dnpztyvoyz) = qvksbumbhp envcilfxeq (xttrjioouf, qecvbotver - auywhlwfag) View more