Delving into the Latest Updates on HRO-761 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

WRN

Action

inhibitors

Mechanism

WRN inhibitors(WRN RecQ like helicase inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesCongenital Disorders+ [1]

Active Indication

Microsatellite instability-high colorectal cancerMicrosatellite Instability-high Solid TumorsMismatch repair-deficient Solid Tumors+ [2]

Inactive Indication-

Originator Organization

Novartis Pharmaceuticals Corp.

Active Organization

China Novartis Institutes for BioMedical Research Co., Ltd.

Novartis Pharmaceuticals Corp.Novartis Pharma AG

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC31H31ClF3N9O5

InChIKeyXKYVECRUZPCRQR-UHFFFAOYSA-N

CAS Registry2869954-34-5

本研究的目的是确定HRO761单药（s.a.）或与抗PD-1抗体替雷利珠单抗或拓扑异构酶抑制剂伊立替康联合用药的安全性、耐受性、药代动力学（PK）、药效学（PD）和抗肿瘤活性。剂量探索部分的主要目的是确定安全、可耐受的剂量和给药方案，并确定HRO761单药或联合用药的推荐剂量（RD）。HRO761单药的剂量探索部分包括剂量递增，随后根据需要进行随机剂量优化。

[Translation]

The purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of HRO761 alone (s.a.) or in combination with the anti-PD-1 antibody tislelizumab or the topoisomerase inhibitor irinotecan. The primary objectives of the dose-finding part are to determine a safe and tolerable dose and dosing schedule and to determine the recommended dose (RD) of HRO761 alone or in combination. The dose-finding part of HRO761 alone includes dose escalation, followed by randomized dose optimization as needed.

Start Date16 Jul 2024

Sponsor / Collaborator

China Novartis Institutes for BioMedical Research Co., Ltd.

[+2]

NCT05838768

/ RecruitingPhase 1

An Open-label, Multi-center Phase I/Ib Dose Finding and Expansion Study of HRO761 as Single Agent and in Combinations in Patients With Microsatellite Instability-High or Mismatch Repair Deficient Advanced Solid Tumors.

The main purpose of the study is to evaluate the safety and tolerability of HRO761 and identify the recommended dose(s), i.e., the optimal safe and active dose of HRO761 alone or in combination with pembrolizumab or irinotecan that can be given to patients who have cancers with specific molecular alterations called MSIhi (Microsatellite Instability-high) or dMMR (Mismatch Repair Deficient) that might work best to treat these specific cancer types and to understand how well HRO761 is able to treat those cancers.

Start Date27 Jun 2023

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with HRO-761

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100 Translational Medicine associated with HRO-761

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100 Patents (Medical) associated with HRO-761

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4

Literatures (Medical) associated with HRO-761

01 May 2025·Bioorganic & Medicinal Chemistry Letters

Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers

Article

Author: Hwang, Jong Yeon ; An, Dongju ; Moon, Byul ; Go, Ahra ; Kim, Jung-Ae ; Park, Seulki ; Lee, Joo-Youn ; Kim, Jeong-Hoon ; Kim, Hyun Jin ; Kim, Jaehoon

The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.

01 Jan 2025·European Journal of Medicinal Chemistry

Design, synthesis, and structure−activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors

Article

Author: Sui, Qibang ; Zhou, Yuanyang ; Zhou, Jingyi ; Teng, Dan ; Li, Manjia ; Zhang, Sulin ; Hou, Hui ; Wang, Xiaofeng ; Liu, Jia ; Zheng, Mingyue ; Cui, Rongrong ; Wang, Dan ; Cai, Xiaoying

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC₅₀ = 16.1 nM, fluorometric helicase assay IC₅₀ = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI₅₀ = 36.4-306 nM), while the GI₅₀ values for multiple microsatellite stability (MSS) cell lines were greater than 20,000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.

09 May 2024·Nature

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

Article

Author: Hamon, Jacques ; Kerr, Grainne ; Schrapp, Maxime ; Zécri, Frédéric ; Gavioli, Elena ; Jaco, Isabel ; Dourdoigne, Marion ; Laborde, Laurent ; Martus, Hans-Joerg ; Andraos-Rey, Rita ; Ferretti, Stephane ; Heuser, Alisa ; Reschke, Markus ; Schaeffer, Fanny ; Strang, Ross ; Hattenberger, Marc ; Bechter, Elisabeth ; Schoepfer, Joseph ; Scheufler, Clemens ; Núñez, Eloísa Jiménez ; Dammassa, Ernesta ; Quadt, Cornelia ; Wartmann, Markus ; Blank, Jutta ; Decker, Andrea ; Romanet, Vincent ; Barbe, Stephanie ; Cortés-Cros, Marta ; Welly, Sarah ; Möbitz, Henrik ; Bordas, Vincent ; Voshol, Hans ; Di Nanni, Noemi ; Hemmerlin, Christelle ; Hinrichs, Jürgen ; de Kanter, Ruben ; Hofmann, Francesco

AbstractThe Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.

100 Deals associated with HRO-761

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Microsatellite Instability-high Solid Tumors	Phase 1	Japan	Novartis Pharma AG	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Taiwan Province	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Israel	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Israel	Novartis Pharma AG	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Norway	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Italy	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Singapore	China Novartis Institutes for BioMedical Research Co., Ltd.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Sweden	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Singapore	Novartis Pharmaceuticals Corp.	27 Jun 2023
Microsatellite Instability-high Solid Tumors	Phase 1	Spain	Novartis Pharmaceuticals Corp.	27 Jun 2023