Saridegib (IPI-926) is a potent and specific inhibitor of Smoothened (Smo), a key transmembrane protein in the Hedgehog signaling pathway. [1]
In a Gli-luciferase reporter assay using C3H10T1/2 cells transfected with wild-type SMO, saridegib inhibited reporter activity with an IC50 of 9 nM. Against the D473H SMO mutant (which confers resistance to another Smo inhibitor GDC-0449), saridegib showed activity with an IC50 of 244 nM. [2]

Saridegib (IPI-926) inhibited Gli-luciferase reporter activity in C3H10T1/2 cells transfected with wild-type SMO with an IC50 of 9 nM, and against the D473H SMO mutant with an IC50 of 244 nM. Reporter activity was normalized to untreated cells. [2]
Western blot analysis showed that saridegib suppressed Gli1 levels in PtcCC medulloblastoma tumors by 83% after 4 days of daily treatment, by 52% after 2 weeks, and by 29% after 6 weeks compared to vehicle-treated control tumors. [2]
P-glycoprotein (Pgp) expression levels in tumor homogenates were significantly increased by daily treatment with saridegib for 6 weeks as measured by Western blotting. [2]
Functional Pgp activity assay using calcein-AM showed that 79.5% of vehicle-treated tumor cells incorporated calcein compared to only 38.6% accumulation in saridegib-treated PtcCC/C tumors, indicating increased efflux activity. The experiment was repeated in the presence of the Pgp inhibitor verapamil, which increased intracellular fluorescence in saridegib-treated tumors, confirming the presence of functional Pgp transporters. [2]
Sequencing analysis of eight brain tumors and three flank tumors from saridegib-treated mice showed no evidence of mutations in transmembrane domains 6 or 7 of Smo. One sequence variation at asparagine 223 was noted, but this is not within any of the seven transmembrane domains nor a known functional domain. PCR analyses of genomic DNA from eight saridegib-resistant brain tumors revealed no Gli2 amplification. Array comparative genomic hybridization showed no focal gains or losses across the entire genome of saridegib-treated tumors compared to normal. [2]
Gene expression profiling using Illumina microarray identified several enriched pathways including those involved in cancer, neurological disease, cell death, and cellular movement. Among Shh subgroup signature genes, SFRP1 was downregulated and OTX2 was upregulated in saridegib-treated tumors. [2]

Saridegib (IPI-926) in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic adenocarcinoma: objective response rate was 67% (9/15 patients). Among 9 patients with elevated baseline CA19-9 (>2x ULN), 6 (66.7%) experienced >50% decline, including 5 with ≥90% decline. Median progression-free survival was 8.4 months. Of 9 patients who continued on maintenance therapy with IPI-926 alone after 8-12 cycles of FOLFIRINOX, 4 showed continued disease stabilization for ≥4 additional months, and 4 of 5 showed continued CA19-9 decline (range 26.9%-97.7%). [1]
In a PtcCC mouse medulloblastoma model (conditional Ptch1-null), 21-day-old symptomatic mice treated with daily intraperitoneal saridegib (20 mg/kg per dose) for 19 days showed complete resolution of clinical symptoms, decreased cerebellar tumor size by gross pathology, reduced tumor burden by Tumor Paint (chlorotoxin:Cy5.5) imaging, and regions of tumor cell death with pyknotic nuclei while retaining normal cerebellar architecture. [2]
In a larger study, 3-5 week-old PtcCC mice with tumors received daily saridegib (20 mg/kg per dose) for 6 weeks (n=26) vs vehicle (n=11). Kaplan-Meier analysis demonstrated 100% survival in the saridegib-treated group vs 0% in vehicle-treated group (P<0.001). Clinical symptoms resolved in many treated mice with restored neurologic function and increased activity. [2]
MRI analysis showed that saridegib treatment induced substantial tumor regression after 3 weeks of daily administration. Average tumor volume decreased from 1,108 mm³ at enrollment to 580 mm³ after 3 weeks (P=0.0005), but increased to 848 mm³ after 6 weeks (P=0.05). Vehicle-treated tumors progressed from 1,082 mm³ to 1,408 mm³ at 3 weeks. [2]
Maintenance dosing study: Mice given daily saridegib (20 mg/kg) for 6 weeks then taken off drug (n=6) showed rapid tumor progression and death within average 10 days. Mice receiving maintenance dosing (20 mg/kg twice per week for additional 6 weeks, n=13) showed 53% survival at 6 weeks after starting twice-weekly therapy. Continued saridegib treatment after 6 weeks of daily therapy prolonged median survival fivefold compared to vehicle-treated controls (P<0.001 for daily then twice-weekly vs vehicle; P=0.001 for daily then twice-weekly vs drug withdrawal). [2]
Flank allograft studies: Tumors established from drug-naive PtcCC donors in 43% (54/127) of recipients. When donors were treated with daily saridegib (20 mg/kg) for 6 weeks before transplantation, only 23% (18/78) of recipients developed flank tumors (P=0.017). Tumors from saridegib-treated donors grew more slowly and often stopped growing; one of six showed spontaneous regression after reaching 895 mm³. [2]
When recipient mice bearing flank allografts (from both drug-naive and saridegib-treated donors) reaching 1,000 mm³ received daily saridegib (20 mg/kg i.p.), tumors became undetectable in 100% of both groups by day 15. However, 2 of 5 tumors from drug-naive donors progressed during the 9-week trial despite initial response. Saridegib concentrations were ~10-15 fold higher in flank tumors than in cerebellar tumors at the same dosing regimen. [2]

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Saridegib (IPI-926) has been shown to enhance mean intratumoral vascular density and decrease tumor-associated stromal tissue in genetically modified mice models of pancreatic cancer. These modifications lead to improved systemic medication delivery when given concurrently, which lowers tumor burden and lengthens survival in this mouse model [1].

Saridegib (IPI-926) Gli-luciferase reporter assay: C3H10T1/2 cells were transfected with wild-type SMO or the D473H SMO mutant. Cells were treated with various doses of saridegib, and average Gli-luciferase reporter activity was measured. Saridegib inhibited reporter activity with an IC50 of 9 nM in cells transfected with wild-type SMO and with an IC50 of 244 nM against the D473H SMO mutant. Reporter activity was normalized to untreated C3H10T1/2 cells. [2]

Saridegib (IPI-926) Gli-luciferase reporter assay: C3H10T1/2 cells were transfected with wild-type SMO or the D473H SMO mutant. After treatment with various doses of saridegib, reporter activity was measured. The IC50 was 9 nM for wild-type SMO and 244 nM for the D473H mutant. [2]
Calcein-AM Pgp functional assay: Untreated and saridegib-treated PtcCC/C medulloblastoma tumor cells were incubated with calcein-AM, a fluorescent Pgp substrate. Intracellular calcein accumulation was measured by flow cytometry. 79.5% of vehicle-treated tumor cells incorporated calcein compared to only 38.6% in saridegib-treated tumors. The experiment was repeated in the presence of the Pgp inhibitor verapamil, which increased intracellular fluorescence in saridegib-treated tumors, confirming functional Pgp transporters. [2]

Saridegib (IPI-926) - Medulloblastoma mouse model (PtcCC mice, conditional Ptch1-null): Mice at postnatal day 21-36 with clinical evidence of medulloblastoma were randomized to receive either saridegib (20 mg/kg per dose) or vehicle control [5% (2-hydroxypropyl)-β-cyclodextrin] administered via daily intraperitoneal injection. Treatment duration ranged from 19 days to 6 weeks. For maintenance studies, after 6 weeks of daily dosing, mice received either drug withdrawal or maintenance dosing (20 mg/kg twice per week intraperitoneal) for an additional 6 weeks. [2]
For combination therapy with verapamil: The ABC transporter inhibitor verapamil (15 mg/kg per dose) was administered weekly via oral gavage between the third and sixth weeks of saridegib treatment. [2]
Flank allograft studies: Medulloblastomas from symptomatic PtcCC mice were harvested, triturated, filtered, and resuspended in equal parts of DMEM and Matrigel. Then 1×10⁶ cells were injected subcutaneously into the flank of wild-type littermates. Tumor volume was calculated from caliper measurements (0.5 × length × width²). Recipient mice bearing flank allografts reaching 1,000 mm³ received either daily saridegib (20 mg/kg i.p.) or vehicle treatment, and tumor growth was monitored over 9 weeks. [2]
Human phase I study (advanced pancreatic adenocarcinoma): Patients received a 7-day run-in period with IPI-926 alone (days -7 to -1). FOLFIRINOX was then administered in 14-day cycles, with bolus 5-FU omitted. Primary prophylaxis with pegfilgrastim or filgrastim was required with each treatment cycle. A 3+3 dose escalation design with 4 dose levels was used to determine maximum tolerated dose. The MTD was identified 1 dose level below standard FOLFIRINOX (dose level 1). Cohort expansion of up to 15 patients at MTD was planned. Patients with stable disease or better after 8-12 cycles of chemotherapy could discontinue FOLFIRINOX while remaining on IPI-926 maintenance therapy alone. [1]
Perfusion CT imaging in a subset of patients: Using a 256-slice multidetector CT scan, jog-mode was used to study an 8-cm longitudinal segment of the upper abdomen centered on the pancreatic tumor mass. After administration of approximately 50 mL of nonionic intravenous contrast, scans with 5-mm slice thickness were obtained at 2-second intervals for 60 seconds with a 5-second post-injection threshold. X-ray parameters were 100 kV with 100 mAs. Perfusion data were analyzed by MISTar software. [1]

Saridegib (IPI-926) - In the human phase I study, drug concentrations of IPI-926 and its main metabolite IPI-541 were measured at predefined time points during the first 5 weeks of study treatment. Plasma levels of IPI-926 far exceeded those of IPI-541 at all time points. Patients reached relative steady-state levels of IPI-926 by the end of the 1-week run-in period. Mean IPI-926 concentration 4 hours post-dose on day 22 (after completing first cycle of FOLFIRINOX) was 188 ng/mL. By comparison, in the first-in-human study of IPI-926 as monotherapy at the same dose, mean Cmax (achieved at 3.13 hours) by day 22 was 336 ng/dL. [1]
In the mouse medulloblastoma model, saridegib concentrations were approximately 10-15 fold higher in flank tumors than in cerebellar tumors at the same dosing regimen (20 mg/kg per day i.p.). Saridegib concentrations in cerebellar tumors increased over time. [2]
Saridegib is known to be a P-glycoprotein (Pgp) substrate. [2]

Saridegib (IPI-926) in combination with FOLFIRINOX in patients with advanced pancreatic adenocarcinoma (N=15): The most common treatment-related adverse events (any grade) included peripheral sensory neuropathy, nausea/vomiting, diarrhea, fatigue, anorexia, and liver function test abnormalities (transaminitis and elevated alkaline phosphatase). Eight of 15 patients (53%) experienced at least one grade 3 or 4 adverse event. Dose-limiting toxicities at dose level 2 (FOLFIRINOX doses identical to PRODIGE study minus 5-FU bolus) occurred in 2 of 6 patients, both related to hepatotoxicity: one with transient elevation in alanine aminotransferase >10× ULN (grade 3) and another with persistent grade 2-3 transaminitis lasting >2 weeks preventing timely administration of cycle 2. Both were reversible after treatment held. The maximum tolerated dose was established as dose level 1 (one dose level below standard FOLFIRINOX). There were no deaths attributable to study treatment. [1]
In the mouse medulloblastoma model, no significant toxicity was reported at the dosing regimen of 20 mg/kg per day intraperitoneal. [2]

[1]. A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. Pancreas. 2016 Mar;45(3):370-5.

[2]. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci U S A . 2012 May 15;109(20):7859-64.

Saridegib (IPI-926) is an oral Hedgehog pathway inhibitor developed by Infinity Pharmaceuticals. [1]
In a genetically engineered mouse model of pancreatic cancer (KPC mouse), IPI-926 depleted the dense desmoplastic mesenchymal stroma and increased intratumoral mean vessel density, enhancing delivery of concurrently administered chemotherapy agents such as gemcitabine, leading to decreased tumor burden and prolonged survival. [1]
The study closed early when a separate phase II trial of IPI-926 plus gemcitabine (IPI-926-03) indicated detrimental effects of this combination, showing shorter median survival and more rapid disease progression compared to placebo plus gemcitabine. A subsequent phase Ib/randomized phase II study of gemcitabine plus another Hh inhibitor (vismodegib) also failed to improve PFS or OS. [1]
Recent preclinical data suggest that depleting the stromal compartment in pancreatic cancer may have detrimental effects, as conditional deletion of Shh in a transgenic mouse model resulted in more aggressive, undifferentiated, and highly proliferative tumors, suggesting tumor stroma may restrain rather than support tumor growth. Long-term treatment with IPI-926 alone or with gemcitabine yielded the same outcome. [1]
In the PtcCC medulloblastoma model, saridegib treatment induced tumor reduction and significantly prolonged survival, with a fivefold increase in lifespan as a single agent compared to vehicle controls. Unlike other Smo inhibitors, drug resistance was not mutation-dependent (no Smo TM6/TM7 mutations or Gli2 amplification) but was associated with increased P-glycoprotein expression and activity. Saridegib remained active against cells with the D473H point mutation that confers resistance to GDC-0449 (vismodegib). [2]

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Saridegib/Patidegib belongs to the piperidine class of drugs. Patidegib has been investigated for the treatment of common chondrosarcoma. Patidegib is a highly bioavailable orally bioavailable cyclic pharmacamine derivative and an inhibitor of the Hedgehog (Hh) signaling pathway, possessing potential antitumor activity. Specifically, Patidegib binds to and inhibits the transmembrane G protein-coupled receptor SMO, thereby suppressing the Hh signaling pathway and reducing tumor cell proliferation and survival. SMO is activated upon binding of Hh ligands to the cell surface receptor Patched (PTCH); aberrant activation of the Hh signaling pathway and uncontrolled cell proliferation may be associated with SMO mutations. The Hh signaling pathway plays a crucial role in the proliferation of neuronal precursor cells in the developing cerebellum and other tissues. Drug Indications: Treatment of nevus-like basal cell carcinoma syndrome (Göring syndrome).

C29H48N2O3S

504.76802

504.339

C, 69.00; H, 9.58; N, 5.55; O, 9.51; S, 6.35

1037210-93-7

1037210-93-7;1169829-40-6 (HCl);

25027363

White to off-white solid powder

6.829

2

5

2

35

988

11

C[C@H]1C[C@@H]2[C@H]([C@H]([C@]3(O2)CC[C@H]4[C@@H]5CC[C@@H]6C[C@@H](CC[C@@]6([C@H]5CC4=C(C3)C)C)NS(=O)(=O)C)C)NC1

HZLFFNCLTRVYJG-WWGOJCOQSA-N

InChI=1S/C29H48N2O3S/c1-17-12-26-27(30-16-17)19(3)29(34-26)11-9-22-23-7-6-20-13-21(31-35(5,32)33)8-10-28(20,4)25(23)14-24(22)18(2)15-29/h17,19-23,25-27,30-31H,6-16H2,1-5H3/t17-,19+,20+,21+,22-,23-,25-,26+,27-,28-,29-/m0/s1

N-[(3R,3'R,3'aS,4aR,6'S,6aR,6bS,7'aR,9S,12aS,12bS)-3',6',11,12b-tetramethylspiro[1,2,3,4,4a,5,6,6a,6b,7,8,10,12,12a-tetradecahydronaphtho[2,1-a]azulene-9,2'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-yl]methanesulfonamide

IPI926; IPI-926; SARIDEGIB; 1037210-93-7; Patidegib; IPI 926

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)