Delving into the Latest Updates on Litronesib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Litronesib (USAN/INN)

+ [2]

Target

KIF11

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [4]

Active Indication-

Inactive Indication

acute leukemiaAdvanced cancerColorectal Cancer+ [9]

Originator Organization

Kyowa Kirin Co., Ltd.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Kyowa Kirin Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H37N5O4S2

InChIKeyYVAFBXLHPINSIK-QHCPKHFHSA-N

CAS Registry910634-41-2

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.

01 Aug 2018·European Journal of Medicinal ChemistryQ1 · MEDICINE

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

Q1 · MEDICINE

Article

Author: Tham, Chuin Lean ; Guglielmi, Paolo ; Karpoormath, Rajshekhar ; Carradori, Simone ; Kozielski, Frank ; Chandrasekaran, Balakumar ; Talapatra, Sandeep K ; Cirilli, Roberto

The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

01 Feb 2017·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer

Q4 · MEDICINE

Article

Author: Leohr, Jennifer ; Shaheen, Montaser ; Burris, Howard A ; Farrington, Daphne L ; Tolcher, Anthony W ; Hynes, Scott M ; Olszanski, Anthony J ; Li, Lily Q ; Verschraegen, Claire F ; Infante, Jeffrey R ; Patnaik, Amita ; Beeram, Muralidhar ; McGlothlin, Anna ; Cohen, Roger B ; Papadopoulos, Kyriakos P ; Lin, Aimee Bence ; Westin, Eric H

PURPOSEThis first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor.METHODSTwo concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m²/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels.RESULTSOne hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m²/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies.CONCLUSIONSOn the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m²/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m²/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.

100 Deals associated with Litronesib

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External Link

KEGG	Wiki	ATC	Drug Bank
D09636	-	-	DB11861

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Esophageal Carcinoma	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Non-Small Cell Lung Cancer	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Ovarian Cancer	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Prostatic Cancer	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Squamous Cell Carcinoma of Head and Neck	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Stomach Cancer	Phase 2	US	Eli Lilly & Co.	01 Apr 2011
Extensive stage Small Cell Lung Cancer	Phase 2	KR	Eli Lilly & Co.	01 Dec 2009
Extensive stage Small Cell Lung Cancer	Phase 2	US	Eli Lilly & Co.	01 Dec 2009
Extensive stage Small Cell Lung Cancer	Preclinical	RO	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


NCT01059643 (CTgov)	Phase 2	Ovarian Cancer \| Esophageal Carcinoma \| Squamous Cell Carcinoma of Head and Neck \| Non-Small Cell Lung Cancer \| Prostatic Cancer \| Colorectal Cancer \| Stomach Cancer	103	pegfilgrastim+LY2523355	jzecbbccoq(ehfdhkdyun) = binsuhbvau atrewyyeij (jskcluuixp, pgjkkeojbw - vikfpolggj) View more	-	04 Dec 2017
NCT01025284 (CTgov)	Phase 2	Extensive stage Small Cell Lung Cancer	64	LY2523355 (Part A)	dcjrpataew(iehaacsqvz) = sqdsepwbgm efyrkbyhgj (rqkvndlknz, jryeesekhb - pgjztbvejt) View more	-	04 Dec 2017
				granulocyte colony-stimulating factor (G-CSF)+LY2523355 (Part B)	oftytqizjo(xkpvkxaykk) = crfstsuktr ajktzvnaww (jxociykjgd, yotrpkqmvy - xtqhfeclsj) View more
NCT01416389 (CTgov)	Phase 2	Metastatic breast cancer	39	pegfilgrastim+LY2523355+filgrastim (LY2523355 + Pegfilgrastim or Filgrastim)	clmoutrkom(xdnncfaasu) = dpshttyyjv ueranogtzb (crhpsnkibl, avbtwatfpy - npacajlylm) View more	-	04 Dec 2017
				ixabepilone (Ixabepilone)	clmoutrkom(xdnncfaasu) = minwthdyce ueranogtzb (crhpsnkibl, pmbatsyyyc - uonjplzfdz) View more
NCT01214642 (Pubmed \| Cancer Chemother Pharmacol) Manual	Phase 1	Advanced cancer	117	litronesib	(vckfhlguqc) = 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. krqthddsur (txvaiuteed ) View more	Positive	01 Feb 2017
				litronesib+pegfilgrastim