Delving into the Latest Updates on CYH33 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Risovalisib

+ [2]

Target

PI3Kα

Mechanism

PI3Kα inhibitors(Phosphatidylinositol 3 kinase alpha inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [4]

Active Indication

Fallopian Tube Clear Cell AdenocarcinomaOvarian clear cell carcinomaPrimary clear cell peritoneal carcinoma+ [4]

Inactive Indication

Advanced breast cancerEndometrial CarcinomaEsophageal Carcinoma+ [8]

Originator Organization

Haihe Biopharma Co., Ltd.

Active Organization

Haihe Biopharma Co., Ltd.

Shanghai Institute of Materia Medica Chinese Academy of Sci

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure

Molecular FormulaC25H33F3N8O8S2

InChIKeyCYWUJTNXNJVGLY-UHFFFAOYSA-N

CAS Registry1494684-33-1

View All Structures (2)

主要目的： - 采用盲态独立评审委员会（BIRC）评估的客观缓解率（ORR）来确定CYH33单药治疗在具有PIK3CA热点突变的复发性或持续性卵巢、输卵管或原发性腹膜透明细胞癌患者中的有效性。将采用顺序检验依次评估主要目的，首先在具有PIK3CA外显子9突变的患者中进行评估，然后在所有PIK3CA热点突变的患者中进行评估。次要目的： - 评价CYH33经BIRC评估的无进展生存期（PFS）、6个月PFS率、缓解持续时间（DoR）、至缓解的时间（TTR）和疾病控制率（DCR）方面的有效性。 - 评价CYH33经研究者评估的ORR、PFS、6个月PFS率、DoR、TTR和DCR方面的有效性。 - 评价总体生存期（OS）获益。

[Translation]

Primary Objectives: - To determine the efficacy of CYH33 monotherapy in patients with recurrent or persistent ovarian, fallopian tube, or primary peritoneal clear cell carcinoma with PIK3CA hotspot mutations using blinded independent review committee (BIRC)-assessed objective response rate (ORR). The primary objectives will be assessed sequentially, first in patients with PIK3CA exon 9 mutations and then in patients with all PIK3CA hotspot mutations, using sequential testing. Secondary Objectives: - To evaluate the efficacy of CYH33 in terms of BIRC-assessed progression-free survival (PFS), 6-month PFS rate, duration of response (DoR), time to response (TTR), and disease control rate (DCR). - To evaluate the efficacy of CYH33 in terms of investigator-assessed ORR, PFS, 6-month PFS rate, DoR, TTR, and DCR. - To evaluate the overall survival (OS) benefit.

Start Date12 Jul 2022

Sponsor / Collaborator

Haihe Biopharma Co., Ltd.

[+1]

CTR20211864 / CompletedPhase 1

一项在中国健康成人中评价食物对CYH33单次给药后的药代动力学特征和安全性影响的临床研究

[Translation] A clinical study to evaluate the effect of food on the pharmacokinetic characteristics and safety of CYH33 after a single dose in healthy Chinese adults

主要目的：评价食物对中国健康成人受试者单次口服CYH33药代动力学特征的影响。次要目的：评价食物对中国健康成人受试者单次口服CYH33安全性的影响。评价CYH33药效动力学生物标志物的变化。

[Translation]

Primary objective: To evaluate the effect of food on the pharmacokinetic characteristics of CYH33 after a single oral dose in healthy Chinese adult subjects. Secondary objective: To evaluate the effect of food on the safety of a single oral dose of CYH33 in healthy Chinese adult subjects. To evaluate the changes in CYH33 pharmacodynamic biomarkers.

Start Date10 Jun 2022

Sponsor / Collaborator

Haihe Biopharma Co., Ltd.

[+1]

CTR20202339 / TerminatedPhase 1

多中心、开放、Ib 期临床试验：评价口服PI3Kα抑制剂CYH33联合PARP抑制剂奥拉帕利在晚期实体瘤患者中的安全性、耐受性、药代动力学和临床疗效

[Translation] A multicenter, open-label, phase Ib clinical trial to evaluate the safety, tolerability, pharmacokinetics and clinical efficacy of the oral PI3Kα inhibitor CYH33 combined with the PARP inhibitor Olaparib in patients with advanced solid tumors

主要目的：确定CYH33联合奥拉帕利在联合奥拉帕利在携带DDR基因突变或PIK3CA突变的晚期实体瘤患者中的MTD或RP2D。评估CYH33联合奥拉帕利在联合奥拉帕利在携带DDR基因突变或PIK3CA突变的5个队列的晚期实体瘤患者中的有效性。次要目的：评价CYH33联合奥拉帕利在晚期实体瘤患者中的安全性和耐受性。评价CYH33联合奥拉帕利的初步有效性。进一步评估CYH33联合奥拉帕利在5个队列中的其他疗效。评价CYH33联合奥拉帕利的药代动力学特征。

[Translation]

Primary objective: To determine the MTD or RP2D of CYH33 combined with Olaparib in patients with advanced solid tumors carrying DDR gene mutations or PIK3CA mutations. To evaluate the efficacy of CYH33 combined with Olaparib in patients with advanced solid tumors carrying DDR gene mutations or PIK3CA mutations in 5 cohorts. Secondary objective: To evaluate the safety and tolerability of CYH33 combined with Olaparib in patients with advanced solid tumors. To evaluate the preliminary efficacy of CYH33 combined with Olaparib. To further evaluate the other efficacy of CYH33 combined with Olaparib in 5 cohorts. To evaluate the pharmacokinetic characteristics of CYH33 combined with Olaparib.

Start Date29 Oct 2021

Sponsor / Collaborator

Haihe Biopharma Co., Ltd.

100 Clinical Results associated with CYH33

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100 Translational Medicine associated with CYH33

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100 Patents (Medical) associated with CYH33

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9

Literatures (Medical) associated with CYH33

12 Apr 2023·Signal transduction and targeted therapy

Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors.

Article

Author: Wang, Yuxiang ; Zhang, Xu ; Hu, Landian ; Yang, Kang ; Shen, Yanyan ; Kong, Xiangyin ; Yang, Biyu ; Ding, Jian ; Meng, Linghua ; Ma, Qingyang ; Wang, Yi ; Zhang, Xi ; Yang, Chunhao ; Shi, Jiajie ; Qiao, Yuemei ; Chen, Yi ; Xu, Lan ; Ge, Gaoxiang

Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

01 May 2022·Clinical and Translational Medicine

Genome‐wide gain‐of‐function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma

Article

Author: Xing, Hui ; Wang, Yuxiang ; Ma, Qingyang ; Kong, Xiangyin ; Meng, Linghua ; Gao, Mengshi ; Yang, Chunhao ; Zhang, Xu ; Shi, Jiajie ; Wang, Xiang ; Liu, Xueling ; Ding, Jian

AbstractPhosphoinositide‐3 kinase alpha (PI3Kα) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3Kα inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome‐wide gain‐of‐function screening with a CRISPR‐SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full‐length EZH2 but not methyltransferase‐deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient‐derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33‐mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient‐derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2‐p21‐RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.

01 Jan 2022·Cancer LettersQ1 · MEDICINE

Repressing MYC by targeting BET synergizes with selective inhibition of PI3Kα against B cell lymphoma

Q1 · MEDICINE

Article

Author: Chun-hao Yang ; Yi Chen ; Zhe-rui Cao ; Yu-xiang Wang ; Zi-qi Chen ; Lan Xu ; Xi Zhang ; Yi Wang ; Jian Ding ; Ling-hua Meng

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.

100 Deals associated with CYH33

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
PIK3CA-related overgrowth syndrome	Phase 2	CN	Haihe Biopharma Co., Ltd.	09 May 2023
PIK3CA-related vascular malformations	Phase 2	CN	Haihe Biopharma Co., Ltd.	09 May 2023
Fallopian Tube Clear Cell Adenocarcinoma	Phase 2	CN	Haihe Biopharma Co., Ltd.	12 Jul 2022
Fallopian Tube Clear Cell Adenocarcinoma	Phase 2	CN	Shanghai Institute of Materia Medica Chinese Academy of Sci	12 Jul 2022
Ovarian clear cell carcinoma	Phase 2	JP	Haihe Biopharma Co., Ltd.	13 Aug 2021
Ovarian clear cell carcinoma	Phase 2	CN	Haihe Biopharma Co., Ltd.	13 Aug 2021
Primary clear cell peritoneal carcinoma	Phase 2	CN	Haihe Biopharma Co., Ltd.	13 Aug 2021
Primary clear cell peritoneal carcinoma	Phase 2	JP	Haihe Biopharma Co., Ltd.	13 Aug 2021
Advanced Malignant Solid Neoplasm	Phase 1	CN	Haihe Biopharma Co., Ltd.	17 May 2018
Esophageal Carcinoma	Preclinical	CN	Haihe Biopharma Co., Ltd.	10 May 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04856371 (Phase Ib study of PI3Kα inhibitor risovalisib mesylate in combination with fulvestrant, ASCO2024)	Phase 1	PIK3CA mutation/HR-positive/HER2-negative Breast Cancer PIK3CA-mutated	52	CYH33 30mg QD + Fulvestrant 500mg	(rdwvmgroxh) = the most common grade 1-2 TRAEs were hyperglycaemia, nausea, decreased appetite, rash, weight decreased, diarrhoea, vomiting, stomatitis, AST increased and ALT increased nimwkkfrms (cjxymspury ) View more	Positive	24 May 2024
NCT03544905 (Pubmed) Manual	Phase 1	PIK3CA H1047R mutant Solid Tumors PIK3CA Mutation	51	CYH33 (overall)	(rkoytdilhu) = slsfavywpm gbhpfcbixd (pekohblyus ) View more	Positive	16 Nov 2022
NCT03544905 (Pubmed) Manual	Phase 1	PIK3CA H1047R mutant Solid Tumors PIK3CA Mutation	51	CYH33 (patients with PIK3CA mutations)	(kzjbjjwlsr) = tcmukrimym blxmybqofr (otjidlgeax )	Positive	16 Nov 2022