Delving into the Latest Updates on XL-888 with Synapse

This phase Ib trial studies the side effects and best dose of Hsp90 inhibitor XL888 when given together with pembrolizumab in treating patients with advanced gastrointestinal cancer that has spread to other places in the body. XL888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving XL888 with pembrolizumab may work better in treating patients with gastrointestinal cancer.

Start Date07 Jul 2017

Sponsor / Collaborator

Emory University

[+4]

NCT02721459 / Active, not recruitingPhase 1IIT

Phase I Study of Escalating Doses of XL888 With Vemurafenib Plus Cobimetinib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

The main purpose of this study is to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered orally with vemurafenib plus cobimetinib in participants with BRAF V600 mutated melanoma and to evaluate the safety and tolerability of this combination.

Start Date07 Sep 2016

Sponsor / Collaborator

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+2]

NCT01657591 / CompletedPhase 1IIT

Phase I Study of Escalating Doses of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

This is a multi-cohort, dose-escalation study of XL888 with a fixed dose of vemurafenib. New dose escalation or de-escalation cohorts will be assigned by the Principal Investigator (PI) with discussion with appropriate co-investigators once safety and tolerability is known for a given cohort in accordance to dose escalation rules. Participants will be defined to be enrolled within a cohort upon receipt of first dose of XL888/vemurafenib.

Start Date27 Jul 2012

Sponsor / Collaborator

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+1]

100 Clinical Results associated with XL-888

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100 Translational Medicine associated with XL-888

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100 Patents (Medical) associated with XL-888

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18

Literatures (Medical) associated with XL-888

13 Sep 2024·Current medicinal chemistry

Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity.

Article

Author: Medrasi, Hanadi Y ; Abbas, Eman M H ; Farghaly, Thoraya A ; Sabour, Rehab ; Alsaiari, Norah A ; Kassem, Asmaa F

BACKGROUND AND OBJECTIVEBreast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).METHODSNovel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90.RESULTSAll tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.CONCLUSIONWe have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.

01 May 2024·Journal of Clinical Investigation

An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis

Article

Author: Zhou, Minqi ; Arkin, Michelle R ; Peng, Tien ; Krasilnikov, Maria ; Ravishankar, Supriya ; Lee, Jin Young ; Wolters, Paul J ; Wilson, Chris ; Ringler, Christian ; Sheppard, Dean ; Pohan, Grace ; Ang, Kenny Kean-Hooi ; Tsukui, Tatsuya ; Reyes, Nabora S

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues, termed senolytics. However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision-cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor, XL888, as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-hi human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mice and humans, respectively, and provides a senolytic screening platform for other age-related diseases.

01 Apr 2024·Cell Chemical Biology

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome

Article

Author: Sylvester, Kayla ; Hughes, Philip F ; Fitzgerald, Michael C ; Derbyshire, Emily R ; Leahy, James W ; Ryan, Daniel H ; Eduful, Benjamin ; Quan, Baiyi ; Chirgwin, Michael E ; Mansfield, Christopher R ; Kafsack, Björn F C ; Haystead, Timothy A J ; Neveu, Gaëlle

The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target.

100 Deals associated with XL-888

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acidemia, Isovaleric	NDA/BLA	US	Merck Sharp & Dohme Corp.	07 Jul 2017
Acidemia, Isovaleric	NDA/BLA	US	Exelixis, Inc.	07 Jul 2017
Colorectal cancer recurrent	NDA/BLA	US	Exelixis, Inc.	07 Jul 2017
Colorectal cancer recurrent	NDA/BLA	US	Merck Sharp & Dohme Corp.	07 Jul 2017
Adenocarcinoma of large intestine	Phase 1	US	Merck Sharp & Dohme Corp.	07 Jul 2017
Colorectal Cancer, Hereditary Nonpolyposis, Type 1	Phase 1	US	Merck Sharp & Dohme Corp.	07 Jul 2017
Colorectal Cancer, Hereditary Nonpolyposis, Type 1	Phase 1	US	Exelixis, Inc.	07 Jul 2017
Pancreatic carcinoma non-resectable	Phase 1	US	Exelixis, Inc.	07 Jul 2017
Pancreatic carcinoma non-resectable	Phase 1	US	Merck Sharp & Dohme Corp.	07 Jul 2017
Unresectable Melanoma	Phase 1	US	Exelixis, Inc.	27 Jul 2012

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03095781 (ESMO_GI2024) Manual	Phase 1	Advanced Colorectal Adenocarcinoma Third line \| \|	16	Pembrolizumab+XL888	(uulhaqzthr) = yttakaexkz pbbbkucsdn (rduxpgryii ) View more	Negative	27 Jun 2024
NCT03095781 (ESMO_GI2024) Manual	Phase 1	Colorectal Cancer RAS \| BRAF \| HER2 amplification	16	Pembrolizumab+XL888	(yjyyozcdsv) = ntppmcvhfi fgghyrntwm (xzvarvgjkr, 3.0 - 9.9) View more	Negative	20 Jun 2024
NCT03095781 (330, SITC2020)	Phase 1/2	Metastatic Digestive System Carcinoma Hsp90 \| PD-1	-	XL888 and pembrolizumab	pazyqnvxdv(bbgndgotfl) = jndivlqcpn bpekzhbonv (rmllnsbiqd )	Positive	10 Dec 2020
NCT03095781 (330, SITC2020)	Phase 1/2	Metastatic Digestive System Carcinoma Hsp90 \| PD-1	-	Pembrolizumab	pazyqnvxdv(bbgndgotfl) = dgbfgcavzc bpekzhbonv (rmllnsbiqd )	Positive	10 Dec 2020
NCT03095781 (ASCO_GI2020) Manual	Phase 1	Neoplasms	-	XL888+pembrolizumab	(myykhtuqct) = XL888 90 mg twice weekly combined with P 200 mg, every 3 weeks pvjwbacrzh (pyoopeluso ) View more	Positive	23 Jan 2020
NCT02721459 (ASCO2019)	Phase 1	Melanoma	25	Vemurafenib 960 mg PO BID + Cobimetinib 60 mg QD for 21 of 28 days + XL888 30 mg PO twice weekly	aetgkymmij(umycdwivaf) = 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose oiyaqscnpa (rjrpuktfzo ) View more	Negative	26 May 2019
NCT02721459 (ASCO2019)	Phase 1	Melanoma	25	Vemurafenib 720 mg PO BID + Cobimetinib 40 mg QD for 21 of 28 days + XL888 60 mg PO twice weekly		Negative	26 May 2019
NCT01657591 (ASCO2016) Manual	Phase 1	Metastatic melanoma BRAF V600 Mutation	19	vemurafenib+XL888	(hocfyeiqkh) = qnwztxhwhl zpqqwvobkv (jgvjmtuhkg, 3.7 - 16.2) View more	Positive	04 Jun 2016