Delving into the Latest Updates on GZ17-6.02 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

TFs and related regulators

Mechanism

Transcription factors inhibitors

Therapeutic Areas

NeoplasmsImmune System DiseasesDigestive System Disorders+ [5]

Active Indication-

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmBasal Cell Carcinoma+ [8]

Originator Organization

Genzada Pharmaceuticals Usa, Inc.

Active Organization-

Inactive Organization

Genzada Pharmaceuticals Usa, Inc.

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

05 Mar 2024·Oncotarget

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

Article

Author: Roberts, Jane L ; Booth, Laurence ; Dent, Paul ; West, Cameron

GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent. The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.

08 Feb 2024·Oncotarget

GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells

Article

Author: Dent, Paul ; Roberts, Jane L ; West, Cameron ; Booth, Michael R ; Booth, Laurence

GZ17-6.02, composed of curcumin, harmine and isovanillin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not been studied. GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. All three components are necessary for optimal killing of MF cells. GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.

100 Deals associated with GZ17-6.02

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 2	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Advanced Malignant Solid Neoplasm	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Basal Cell Carcinoma	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Cutaneous Squamous Cell Carcinoma	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Cutaneous T-Cell Lymphoma	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Hormone receptor positive breast cancer	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Metastatic Prostate Carcinoma	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Pancreatic Cancer	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Squamous Cell Carcinoma of Head and Neck	Phase 1	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019
Sarcoma	Discovery	US	Genzada Pharmaceuticals Usa, Inc.	01 Mar 2019