Inavolisib

Inavolisib

WeightAverage: 407.378
Monoisotopic: 407.140510438

Chemical FormulaC₁₈H₁₉F₂N₅O₄

GDC-0077
CAS 2060571-02-8
GDC0077
RG6114
WHO 11204
GDC 0077
GDC-0077
RG-6114
RG6114
RO-7113755
RO7113755

FDA APPROVED, 10/10/2024, Itovebi, To treat locally advanced or metastatic breast cancer
Drug Trials Snapshot

(2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide

(2S)-2-((2-((4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl)-5,6-dihydroimidazo(1,2-D)(1,4)benzoxazepin-9-yl)amino)propanamide
propanamide, 2-((2-((4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl)-5,6-dihydroimidazo(1,2-D)(1,4)benzoxazepin-9-yl)amino)-, (2S)-

Inavolisib, sold under the brand name Itovebi, is an anti-cancer medication used for the treatment of breast cancer.^[2]^[3] It is an inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha.^[4] The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.^[5]

The most common adverse reactions include decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.^[3]

Inavolisib was approved for medical use in the United States in October 2024.^[3]^[6]^[7]

SYN

Hanan EJ, Braun MG, Heald RA, MacLeod C, Chan C, Clausen S, Edgar KA, Eigenbrot C, Elliott R, Endres N, Friedman LS, Gogol E, Gu XH, Thibodeau RH, Jackson PS, Kiefer JR, Knight JD, Nannini M, Narukulla R, Pace A, Pang J, Purkey HE, Salphati L, Sampath D, Schmidt S, Sideris S, Song K, Sujatha-Bhaskar S, Ultsch M, Wallweber H, Xin J, Yeap S, Young A, Zhong Y, Staben ST: Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kalpha. J Med Chem. 2022 Dec 22;65(24):16589-16621. doi: 10.1021/acs.jmedchem.2c01422. Epub 2022 Dec 1.

PATENT

US10112932, Compound 101

https://patentscope.wipo.int/search/en/detail.jsf?docId=US215633239&_cid=P11-M9XU5W-08686-1

Example 101 (S)-2-((2-((S)-4-(Difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide 101

Step 1: 4-Bromo-2-hydroxybenzaldehyde

Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 3-bromophenol (1300 g, 7.51 mol), dichloromagnesium (1078 g, 11.3 mol), triethylamine (3034 g, 30.0 mol) and acetonitrile (7.8 L). The mixture was stirred for 30 minutes at 40° C. To the mixture was added paraformaldehyde (676 g, 22.6 mol) at 80° C. The resulting solution was stirred for 6 hours at 76° C. This reaction was repeated 5 times. The combined reaction mixtures were quenched by the addition of 12 L of aqueous hydrogen chloride (4 N). The pH value of the solution was adjusted to 5 with concentrated aqueous hydrogen chloride (12 N). The resulting solution was extracted with 1×20 L of ethyl acetate. The organic extracts were evaporated in vacuo. The residue was purified via flash chromatography on silica gel (eluted: 15% ethyl acetate in petroleum ether) to give crude product which was washed with 2.4 L of methyl tert-butyl ether:hexane (1:4). The resultant solids were collected by filtration to yield 7.0 kg (78%) of the title compound as a yellow solid.

Step 2: 5-Bromo-2-(1H-imidazol-2-yl)phenol

Into a 20 L 4-necked round-bottom flask was placed a solution of 4-bromo-2-hydroxybenzaldehyde (700 g, 3.50 mol) in methanol (7.0 L) and oxaldehyde (40%) (2540 g, 17.5 mol) followed by the dropwise addition over 4 hours of aqueous ammonia (25-28%, 3500 g) with stirring and maintaining the temperature below 40° C. The resulting solution was stirred for 15 hours at 30-35° C. This reaction was repeated 9 times. The combined 9 reaction mixtures were evaporated in vacuo keeping the temperature below 45° C. The residue was diluted with 100 L of ethyl acetate with stirring for 30 minutes. The solids were filtered out and the resulting solution was diluted with water. The aqueous phase was extracted with 35 L of ethyl acetate. The organic extracts were evaporated under vacuum and the residue was purified via flash chromatography on silica gel (solvent gradient: 5-75% ethyl acetate in petroleum ether) to yield 2.4 kg (29%) of the title compound as a yellow solid.

Step 3: 9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Into a 20 L 4-necked round-bottom flask was placed a solution of 5-bromo-2-(1H-imidazol-2-yl)phenol (1.4 kg, 5.86 mol) in N,N-dimethylformamide (14 L) and cesium carbonate (7.2 kg, 22.1 mol). The mixture was stirred for 20 minutes. To the reaction mixture was added 1,2-dibromoethane (4.1 kg, 21.8 mol). The resulting solution was stirred for 4-12 hours at 85-90° C., cooled to 15° C., and filtered. The filter cake was washed with 3.0 L of ethyl acetate. The filtrate was diluted with 14 L of ethyl acetate. The combined organic extracts were washed with brine (4×14 L), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 1.1 kg (71%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺=265; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.32 (d, J=8.4, 1H), 7.35-7.24 (m, 3H), 7.06 (s, 1H), 4.47-4.42 (m, 4H).

Step 4: 9-Bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Into a 20 L 4-necked round-bottom flask was placed 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (2.5 kg, 9.43 mol) and N,N-dimethylformamide (12.5 L) followed by the addition of N-iodosuccinimide (6.0 kg, 26.7 mol) in several batches with stirring. The resulting solution was stirred for 12 hours at 60° C., cooled to 15° C. with a water/ice bath, diluted with 12.5 L of water/ice, and filtered. The filtered solids were recrystallized from petroleum ether to yield 4.0 kg (82%) of the title compound as a yellow solid.

Step 5: 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d]j[1,4]oxazepine (800 g, 1.55 mol) and tetrahydrofuran (2.4 L) followed by the dropwise addition of ethyl magnesium bromide (1 N solution in ether, 1.7 L) with stirring at −20° C., over 3.5 hours. The reaction mixture was stirred for 3 hours keeping the temperature at −15° C. using an ice/salt bath. The resultant mixture was quenched by the addition of 3.0 L of saturated aqueous ammonium chloride, and extracted with ethyl acetate (2×8.0 L). The combined organic extracts were washed with brine (2×10 L), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude residue was triturated with 8.0 L of ethyl acetate:petroleum ether (1:5), filtered, and washed with petroleum ether to yield 501 g (83%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺=391; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.22 (d, J=8.7, 1H), 7.55 (s, 1H), 7.30-7.25 (m, 2H), 4.45-4.41 (m, 4H).

Step 6: (R)-2,2-Dimethyl-[1,3]dioxolane-4-carbaldehyde

Sodium periodate (57.0 g, 270 mmol) was dissolved in hot water (115 mL) and silica (200 g, 60 Å 220-440 mesh, particle size 35-75 μm) was added. The mixture was stirred vigorously until a free flowing powder was obtained. This was added to a solution of 1,2:5,6-bis-O-(1-methylethylidene)-D-mannitol (50 g, 190 mmol) in dichloromethane (1.0 L) and the reaction was stirred at room temperature for 1 hour. The resultant mixture was filtered through a pad of Na ₂SO ₄and the solids washed thoroughly with dichloromethane. The combined organic extracts were evaporated in vacuo to yield 37.2 g (75%) of the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl ₃) δ 9.73 (d, J=1.9 Hz, 1H), 4.38 (ddd, J=7.4, 4.7, 1.9 Hz, 1H), 4.18 (dd, J=8.8, 7.4 Hz, 1H), 4.10 (dd, J=8.8, 4.7 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 3H).

Step 7: (R)-4-Difluoromethyl-2,2-dimethyl-[1,3]dioxolane

To a solution of (R)-2,2-dimethyl-[1,3]dioxolane-4-carbaldehyde (7.08 g, 54 mmol) in dichloromethane (50 mL) cooled in a water bath was added, dropwise, diethylaminosulfur trifluoride (8.4 mL, 62.6 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The resultant mixture was added dropwise to a rapidly stirring, ice cold saturated aqueous sodium bicarbonate solution. The mixture was further extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to yield 6.58 g (79%) of the crude title compound as an orange oil. ¹H NMR (400 MHz, CDCl ₃) δ 5.69 (td, J=55.8, 4.9 Hz, 1H), 4.27-4.17 (m, 1H), 4.16-4.03 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).

Step 8: (R)-3-(tert-Butyldimethylsilanyloxy)-1,1-difluoropropan-2-ol

HCl in dioxane (4 N, 10.8 mL, 43.2 mmol) was added to a solution of (R)-4-difluoromethyl-2,2-dimethyl[1,3]dioxolane (6.58 g, 43.2 mmol) in methanol (40 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was evaporated in vacuo and azeotroped with acetonitrile. The residue was dissolved in N,N-dimethylformamide (10 mL) and tert-butyldimethylsilyl chloride (6.53 g, 43.2 mmol), triethylamine (9.0 mL, 64.9 mmol) and 4-(dimethylamino)pyridine (catalytic) were added. The reaction mixture was stirred at room temperature for 1 hour. The resultant mixture was washed with water and then extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resultant crude residue was purified via flash chromatography on silica gel (solvent gradient: 0-30% ethyl acetate in cyclohexane) to yield 3.43 g (35%) of the title compound as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) 5.66 (td, J=56.4, 4.6 Hz, 1H), 3.76-3.60 (m, 2H), 2.46 (d, J=6.4 Hz, 1H), 0.81 (s, 9H), 0.00 (s, 6H).

Step 9: ((S)-2-Azido-3,3-difluoropropoxy)-tert-butyldimethylsilane

Trifluoromethanesulfonic anhydride (2.9 mL, 17.4 mmol) was added dropwise to a solution of (R)-3-(tert-butyldimethylsilanyloxy)-1,1-difluoropropan-2-ol (3.43 g, 15.1 mmol) and pyridine (2.0 mL, 24.2 mmol) in dichloromethane (50 mL) at −20° C. and the reaction mixture stirred at −20° C. for 20 minutes and then at 0° C. for 1 hour. The resultant mixture was diluted with 0.5 N aqueous HCl and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was dissolved in N,N-dimethylformamide (10 mL), sodium azide (2.96 g, 45.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to yield 4.50 g of the crude title compound. ¹H NMR (400 MHz, CDCl ₃) δ 5.74 (td, J=55.4, 4.4 Hz, 1H), 3.81-3.71 (m, 2H), 3.58-3.47 (m, 1H), 0.81 (s, 9H), 0.00 (s, 6H).

Step 10: (S)-1-(tert-Butyldimethylsilanyloxymethyl)-2,2-difluoroethylamine

Palladium hydroxide on carbon (200 mg, 20%) was added to a solution of ((R)-2-azido-3,3-difluoropropoxy)-tert-butyldimethylsilane (4.50 g, crude, assume ˜15.1 mmol) in ethyl acetate (20 mL) and methanol (2.0 mL) and the reaction stirred under a balloon of hydrogen for 16 hours. The reaction was filtered, fresh palladium hydroxide on carbon (400 mg, 20%) added and the reaction mixture was stirred under a balloon of hydrogen for 16 hours. The resultant mixture was filtered and the filtrate was evaporated in vacuo to yield 3.08 g (90%) of the crude title product as a colorless oil. ¹H NMR (400 MHz, CDCl ₃) δ 5.66 (td, J=57.0, 4.7 Hz, 1H), 3.71-3.57 (m, 2H), 3.00-2.89 (m, 1H), 1.42 (br s, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

Step 11: (S)-4-Difluoromethyloxazolidin-2-one

HCl in dioxane (4 N, 5.0 mL, 20 mmol) was added to a solution of (R)-1-(tert-butyldimethylsilanyloxymethyl)-2,2-difluoroethylamine ( Org. Lett., Vol. 9, No. 1, 2007, 41-44) (2.30 g, 10.3 mmol) in methanol (5.0 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and the resultant oil was triturated with diethyl ether to give a solid which was dried in vacuo. The solid was dissolved in a mixture of toluene (20 mL) and KOH (2.50 g, 44.6 mmol in 20 mL water) at 0° C. Phosgene (16.3 mL, 20% in toluene) was added dropwise, the cooling bath was removed and the reaction mixture was stirred for 1 hour. The mixture was evaporated in vacuo, the resultant residue was extracted with hot industrial methylated spirits and the solid was collected by filtration. The filtrate was evaporated in vacuo and the resultant residue was purified via flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate in cyclohexane) to yield 830 mg (68%) of the title compound as an off-white solid. [α] _D=+10.1 (c=2.37, CHCl ₃). ¹H NMR (400 MHz, CDCl ₃) δ 5.96 (br s, 1H), 5.78 (td, J=55.3, 4.8 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 4.42 (dd, J=9.6, 4.4 Hz, 1H), 4.17-4.06 (m, 1H).

Step 12: (S)-3-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one

A mixture of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (250 mg, 0.64 mmol), (S)-4-difluoromethyloxazolidin-2-one (88 mg, 0.64 mmol), trans-N,N′-dimethyl-1,2-cyclohexane diamine (36 mg, 0.26 mmol), cuprous iodide (24 mg, 0.13 mmol) and potassium carbonate (177 mg, 1.28 mmol) in dioxane (3.0 mL) was degassed with argon under sonication. The reaction mixture was heated at 100° C. for 5 h and then allowed to cool to room temperature. The resultant mixture was diluted with 15% aqueous ammonia and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was triturated with methanol and then purified via preparative HPLC [C18, 60% acetonitrile (0.1% formic acid) in water (0.1% formic acid), 20 minute run] to yield 20 mg (8%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺=400/402. ¹H NMR (400 MHz, CDCl ₃) δ 8.19 (d, J=9.2 Hz, 1H), 7.29 (s, 1H), 7.24-7.19 (m, 2H), 6.65 (ddd, J=57.8, 54.5, 1.0 Hz, 1H), 4.87 (ddd, J=24.0, 9.2, 4.0 Hz, 1H), 4.73 (dd, J=9.5, 4.2 Hz, 1H), 4.53 (t, J=9.2 Hz, 1H), 4.48-4.43 (m, 2H), 4.38-4.33 (m, 2H).

Step 13: (S)-2-((2-((S)-4-(Difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-3-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (600 mg, 1.50 mmol), L-alanine (267 mg, 3.00 mmol), cuprous iodide (57 mg, 0.30 mmol) and potassium phosphate tribasic (637 mg, 3.00 mmol) were suspended in dimethyl sulfoxide (6.0 mL). The reaction mixture was heated at 100° C. for 2 hours. Upon allowing to cool to room temperature, dimethyl sulfoxide (4.0 mL), ammonium chloride (480 mg, 9.00 mmol), and triethylamine (3.1 mL, 22.5 mmol) were added. To the resultant stirred suspension was added, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (5.10 g, 13.5 mmol), portion-wise over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour and then filtered through Celite®, washing with ethyl acetate. The organic extracts were washed with saturated aqueous sodium bicarbonate and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified via flash chromatography on silica gel (solvent gradient: 0-5% methanol in dichloromethane) and then by chiral supercritical fluid chromatography to yield 294 mg (46%) of 101 as an off-white solid. LCMS (ESI): R _T(min)=2.89 [M+H] ⁺=408, Method=A; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.00 (d, J=8.7 Hz, 1H), 7.38 (br s, 1H), 7.18 (s, 1H), 7.00 (br s, 1H), 6.71 (t, J=55.9 Hz, 1H), 6.41 (dd, J=8.8, 2.3 Hz, 1H), 6.16 (d, J=7.2 Hz, 1H), 6.09 (d, J=1.9 Hz, 1H), 5.02-4.89 (m, 1H), 4.63-4.52 (m, 2H), 4.39-4.30 (m, 4H), 3.76 (quintet, J=7.0 Hz, 1H), 1.30 (d, J=7.1 Hz, 3H).

Medical uses

Inavolisib is indicated in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.^[3]

Side effects

History

Efficacy was evaluated in INAVO120 (NCT04191499), a randomized, double-blind, placebo-controlled, multicenter trial in 325 participants with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within twelve months of completing adjuvant endocrine therapy and who had not received prior systemic therapy for locally advanced or metastatic disease.^[3] Primary endocrine resistance was defined as relapse while on the first two years of adjuvant endocrine therapy (ET) and secondary endocrine resistance was defined as relapse while on adjuvant ET after at least two years or relapse within twelve months of completing adjuvant ET.^[3]

Structure, reactivity, and synthesis

Inavolisib is a synthetic, organic, small compound (the full structure can be seen here).^[8] When binding to phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α), inavolisib’s carbonyl group can accept a hydrogen bond from the Tyr836 (conserved) in p110α. The difluoromethyl group can interact with the hydroxyl group presented on Ser774 (conserved) in p110α, which is 3.2Å nearer than of which on the equivalent residue Ser754 in p110δ. Additionally, the amide group can interact with Gln859 (non-conserved). This results in a very high selectivity regarding PI3Kα isoforms.^[4]^[9]

Compared to similar PI3K inhibiting compounds, inavolisib has a higher thermodynamic aqueous solubility that proved advantageous in the formulation process and aiding greater consistency in predictions of absorption.^[4]

Inavolisibcan be developed as a derivative of 1,3-oxazole^[10] or by means of stereo-controlled N-arylation of alpha-amino acids.^[11]

Metabolism and biotransformation

Inavolisib is orally administered, though there is little knowledge about its metabolism.^[12]However, absorption, metabolism, and excretion data of taselisib, a molecule with a related chemical scaffold, suggest moderately slow absorption into the systemic circulation, metabolism to play a minor role in drug clearance, and biliary excretion to be the main route of excretion.^[13]

Molecular mechanisms of action

Inavolisib is a selective PI3K-p110α (PIK3CA) inhibitor, which may offer antineoplastic functionality.^[8] Therefore, it may serve as a new addition to combination therapy with conventional cancer treatment, such as chemotherapy. Combining inavolisib with palbociclib and fulvestrant might improve treatment of breast cancer.^[14]

Next to its inhibitory enzymatic ability, it is suggested that inavolisib binds to – and activates degradation of – mutated forms of p110α. Members of the PI3K family regulate cellular processes such as cell growth and proliferation, survival, remodelling, and intracellular transport of organelles.^[15] PI3K also plays an essential role for the immune system.

The class I isoform PI3K alpha (PI3Kα) is often times expressed in solid tumours through gene amplification or activated mutations.^[4] Mutations in PI3Kα can often be found in cancer cells, especially HR+ breast cancer, which causes a disruption of the PI3K pathway. This leads to increased tumour growth and metastasis. One of the most common mutations can be found in PIK3CA, which plays a significant role in tumour cell proliferation.

In preclinical studies, inavolisib has shown to specifically initiate the degradation of this p110α oncogene with the help of proteasomes.^[16] After binding to the mutant PI3Kα, inavolisib blocks phosphorylation of PIP₂ to PIP₃, thereby stopping downstream signalling.^[17]

Consequently, biomarkers in the PI3K pathway are reduced, cell proliferation inhibited, and the rate of PIK3CA-mutant breast cancer apoptosis increased (in comparison to the wild type). The exact mechanism of action of inhibitors like inavolisib on mutated PI3Kα and the inhibitors’ influence on mutant structures are still unknown.^[18]

Toxicity

Inavolisib is able to induce a cytotoxic response but this is directed towards tumour cells that contain the PI3K mutation, thereby inhibiting further tumour growth and leading to cell loss.^[19]

Society and culture

Legal status

In October 2024, the US Food and Drug Administration (FDA) approved inavolisib for the treatment of PIK3CA-mutant breast cancer based on the results from the INAVO120 trial.^[3]^[6]^[20]^[21] The drug application was granted priority review and breakthrough therapy designations by the FDA.^[3]

Names

Inavolisib is the international nonproprietary name.^[22]^[23]

Inavolisib is sold under the brand name Itovebi.^[3]

Research

Due to inavolisib’s ability to inhibit the PI3K pathway through HER2-dependent degradation, it is undergoing clinical trials to potentially make use of it as an antineoplastic (anti-cancer) drug to treat breast cancer.^[4]^[24]^[17]

References

^ “Register of Innovative Drugs”. Health Canada. 3 November 2006. Retrieved 17 April 2025.
^ Jump up to:^a ^b “Itovebi- inavolisib tablet, film coated”. DailyMed. 11 October 2024. Retrieved 11 November 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer”. U.S. Food and Drug Administration (FDA). 10 October 2024. Retrieved 11 October 2024. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e Hanan EJ, Braun MG, Heald RA, MacLeod C, Chan C, Clausen S, et al. (December 2022). “Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα”. Journal of Medicinal Chemistry. 65 (24). American Chemical Society (ACS): 16589–16621. doi:10.1021/acs.jmedchem.2c01422. PMID 36455032. S2CID 254149451.
^ “CID 124173720, Inavolisib”. PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 21 September 2023.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Jump up to:^a ^b “inavolisib — Ligand page”. IUPHAR/BPS Guide to Pharmacology. Retrieved 21 September 2023.
^ Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K (October 2021). “PI3K inhibitors are finally coming of age”. Nature Reviews. Drug Discovery. 20 (10). Springer Science and Business Media LLC: 741–769. doi:10.1038/s41573-021-00209-1. PMC 9297732. PMID 34127844.
^ Chen J, Lv S, Liu J, Yu Y, Wang H, Zhang H (December 2021). “An Overview of Bioactive 1,3-Oxazole-Containing Alkaloids from Marine Organisms”. Pharmaceuticals. 14 (12). MDPI AG: 1274. doi:10.3390/ph14121274. PMC 8706051. PMID 34959674.
^ Han C, Kelly SM, Cravillion T, Savage SJ, Nguyen T, Gosselin F (2019). “Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino acids”. Tetrahedron. 75 (32). Elsevier BV: 4351–4357. doi:10.1016/j.tet.2019.04.057. ISSN 0040-4020. S2CID 150262658.
^ “Inavolisib: Uses, Interactions, Mechanism of Action”. DrugBank. 20 May 2019. DB15275. Retrieved 21 September 2023.
^ Ma S, Cho S, Sahasranaman S, Zhao W, Pang J, Ding X, et al. (April 2023). “Absorption, Metabolism, and Excretion of Taselisib (GDC-0032), a Potent β-Sparing PI3K Inhibitor in Rats, Dogs, and Humans”. Drug Metabolism and Disposition. 51 (4): 436–450. doi:10.1124/dmd.122.001096. PMID 36623882.
^ “A trial looking at a new drug called inavolisib for breast cancer that has spread (WO41554)”. Cancer Research UK. 22 June 2021. Retrieved 21 September 2023.
^ Koyasu S (April 2003). “The role of PI3K in immune cells”. Nature Immunology. 4 (4). Springer Science and Business Media LLC: 313–319. doi:10.1038/ni0403-313. PMID 12660731. S2CID 9951653.
^ Hong R, Edgar K, Song K, Steven S, Young A, Hamilton P, et al. (15 February 2018). “Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies”. Cancer Research. 78 (4_Supplement). American Association for Cancer Research (AACR): PD4–14–PD4–14. doi:10.1158/1538-7445.sabcs17-pd4-14. ISSN 0008-5472.
^ Jump up to:^a ^b “Inavolisib (PI3K alpha inhibitor)”. Genentech. Retrieved 21 September 2023.
^ Menteş M, Karakuzulu BB, Uçar GB, Yandım C (August 2022). “Comparative molecular dynamics analyses on PIK3CA hotspot mutations with PI3Kα specific inhibitors and ATP”. Computational Biology and Chemistry. 99. Elsevier BV: 107726. doi:10.1016/j.compbiolchem.2022.107726. PMID 35842959. S2CID 250404770.
^ Song KW, Edgar KA, Hanan EJ, Hafner M, Oeh J, Merchant M, et al. (January 2022). “RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy”. Cancer Discovery. 12 (1). American Association for Cancer Research (AACR): 204–219. doi:10.1158/2159-8290.cd-21-0072. PMC 9762331. PMID 34544753.
^ “FDA Approves Genentech’s Itovebi, a Targeted Treatment for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer With a PIK3CA Mutation” (Press release). Genentech. 10 October 2024. Retrieved 11 October 2024 – via Business Wire.
^ “U.S. Food and Drug Administration Approves FoundationOne Liquid CDx as a Companion Diagnostic for Itovebi (inavolisib) to Identify Patients with Hormone Receptor-Positive, HER2-Negative Breast Cancer with a PIK3CA Mutation” (Press release). Foundation Medicine. 11 October 2024. Retrieved 11 October 2024 – via Business Wire.
^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 84”. WHO Drug Information. 34 (3). hdl:10665/340680.
^ World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90”. WHO Drug Information. 37 (3). hdl:10665/373341.
^ Vanhaesebroeck B, Burke JE, Madsen RR (January 2022). “Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation”. Cancer Discovery. 12 (1). American Association for Cancer Research (AACR): 20–22. doi:10.1158/2159-8290.cd-21-1411. PMC 7612218. PMID 35022207.

External links

Clinical trial number NCT04191499 for “A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120)” at ClinicalTrials.gov

Clinical data

Trade names	Itovebi
Other names	GDC-0077, RG6114, Ro7113755
AHFS/Drugs.com	Itovebi
License data	US DailyMed: Inavolisib
Routes of administration	By mouth
Drug class	PI3K inhibitor
ATC code	None
Legal status
Legal status	CA: ℞-only^[1]US: ℞-only^[2]
Identifiers
showIUPAC name
CAS Number	2060571-02-8
PubChem CID	124173720
IUPHAR/BPS	9636
DrugBank	DB15275
ChemSpider	59718498
UNII	L4C1UY2NYH
KEGG	D11942
ChEMBL	ChEMBL4650215
PDB ligand	X3N (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₈H₁₉F₂N₅O₄
Molar mass	407.378 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

//////////Inavolisib, FDA 2024, APPROVALS 2024, GDC-0077, 2060571-02-8, GDC0077, RG6114, WHO 11204, GDC 0077, GDC-0077, RG-6114, RG6114, RO-7113755, RO7113755