RU2812708C2 - USE OF COMPOSITIONS BASED ON BRaf INHIBITOR FOR EXTERNAL USE FOR TREATMENT OF RADIATION DERMATITIS - Google Patents

Abstract

FIELD: oncology.

SUBSTANCE: invention relates to a method of treating, preventing and/or reducing the intensity of radiation dermatitis caused by radiation therapy. The following is proposed: the use in a subject in need of a composition for external use containing a therapeutically or prophylactically effective amount of at least one BRaf inhibitor.

EFFECT: provides reduction in severity or prevention of worsening of radiation dermatitis.

16 cl, 6 dwg, 7 ex

Description

This application claims benefit from U.S. Provisional Patent Application Serial No. 62/804,235, filed February 12, 2019, the entire contents of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

The present invention relates to methods of treating radiation dermatitis by administering to a subject in need thereof a composition comprising a therapeutically and/or prophylactically effective amount of at least one BRaf inhibitor or combination thereof and a pharmaceutically acceptable carrier or excipient.

State of the art

Radiotherapy (RT) remains an important component in cancer treatment, with nearly 50% of patients with cancer receiving RT at some point during their disease. Of those who receive RT, up to 95% may suffer some form of radiation dermatitis or radiation skin damage. Radiation dermatitis may manifest as acute erythema and desquamation, or chronic effects including skin atrophy, telangiectasia, and fibrosis. These skin changes are caused by a combination of RT properties and the patient's internal risk factors. Although reducing the overall radiation dose and using improved radiation delivery methods can help reduce the severity of radiation exposure to the skin, radiation dermatitis is still one of the most common side effects of RT. This condition can affect the patient's quality of life both during and after treatment. In severe cases, there is a risk of limiting the radiation dose or interrupting the course of treatment, which may negatively affect the effectiveness of treatment. Therefore, measures to manage radiation skin damage during and after treatment are an important aspect of cancer care. Despite technological advances in radiation delivery methods and growing interest in measures to manage skin reactions, there is no gold standard for the management of radiation dermatitis.

Radiation dermatitis can be a side effect of radiation therapy for some benign tumors.

There is an unmet need in the field to develop new prevention and treatment options that would help alleviate radiation-induced dermatitis during and after treatment.

BRaf is a protein kinase involved in the regulation of the mitogen-activated protein kinase (MAPK) signaling pathway and cell proliferation. BRaf mutations can induce constitutive signaling within the MAPK pathway, which may result in uncontrolled cell proliferation and malignancy.

It has been demonstrated that the use of BRaf inhibitors is associated with inhibition of MAPK signaling, which can be determined by inhibition or reduction in the level of phosphorylated ERK, which is a downstream effector of BRaf signaling. However, it has also been found that, paradoxically, BRaf inhibitors can induce the opposite effect of activating MAPK signaling in wild-type cells relative to BRAF and inducing cell proliferation. (N. Shelach, US Patent Application No. 20180369247).

Disclosure of the Invention

The present disclosure relates to methods of treating radiation dermatitis by administering to a subject in need thereof a composition comprising a prophylactically and/or therapeutically effective topical amount of at least one Group A-D BRaf inhibitor as defined herein. The present disclosure also relates to compositions containing BRaf inhibitors of groups A-D, and methods of treating radiotherapy-induced dermatological adverse reactions using BRaf inhibitors and compositions based thereon for topical use according to the present disclosure.

Brief description of drawings

In fig. 1 shows the effects of compound C-1 on MIA PaCa cell proliferation.

In fig. 2 shows the effects of the compound vemurafenib on MIA PaCa cell proliferation.

In fig. 3 shows the effects of compound LUT-012 on the proliferation of MIA PaCa cells.

In fig. 4 shows the effects of compound LUT-013 on the proliferation of MIA PaCa cells.

In fig. 5 shows the effects of compound LUT-014 on MIA PaCa cell proliferation.

In fig. 6 shows the effects of compound LUT-015 on MIA PaCa cell proliferation.

Carrying out the invention

Presented herein are methods of treating radiation dermatitis using BRaf inhibitors and topical compositions thereof according to the present disclosure.

Radiation dermatitis, also known as radiation dermatitis, x-ray dermatitis, radiation skin damage or radiation burn, is a side effect of radiation therapy, primarily used to treat cancer. Its symptoms include redness, itching, flaking, flaking, soreness, blistering, fibrosis, scarring and skin ulcers. These are serious symptoms that can negatively affect the patient's desire to continue treatment and his/her quality of life.

Radiation dermatitis continues after completion of radiation therapy, and therefore treatment must be continued.

There are several known treatments for radiation dermatitis: skin emollients, corticosteroids, moist dressings, injectable amifostine and silver-based dressings/ointments, and antibiotics to treat secondary skin infections. Of the above-mentioned known treatments, amifostine is probably the most effective, but the injection route of administration has its disadvantage.

The present inventors concluded that topical BRaf inhibitors could be used to treat radiation dermatitis based on mechanism-related arguments for the well-known paradoxical effect.

Related patent application PCT/IL2017/050301 entitled “Use of BRaf Inhibitors for Treating Cutaneous Reactions” by N. Shelach shows that this paradoxical MAPK activation may be used for the treatment of adverse skin reactions induced by treatment with EGFR or PI3K inhibitors.

Without being bound by theory, we propose that another aspect of this same mechanism may provide the basis for the treatment of radiation dermatitis with topical BRaf inhibitors. This is likely due to the positive effect of BRaf inhibitors on cell proliferation (see Example 1).

Application of BRaf inhibitors to BRaf mutant cells has been demonstrated to be associated with inhibition of cell proliferation, which is a downstream effector function of BRaf and MAPK.

However, it has been found that BRaf inhibitors can paradoxically induce the opposite effect of activating MAPK signaling and inducing cell proliferation in wild-type cells relative to BRaf. The underlying mechanisms of paradoxical MAPK activation have been attributed to dimerization of wild-type BRaf and c-Raf and transactivation of uninhibited Raf protein, leading to subsequent activation of the MAPK signaling pathway and cell proliferation.

Carnahan J. et al. (Mol. Cancer Ther. 9(8) August 2010) demonstrated that selective and potent Raf inhibitors can paradoxically stimulate normal cell proliferation. For a number of orally bioavailable kinase inhibitors disclosed by Smith AL et al., J. Med. Chem. 2009, 52, 6189-6192, has been shown to have potent biochemical activity. For example, compound 1 of series (C-1) showed significant efficacy ( ^WT B-Raf Ki = 1 nmol/L, V600EB-Raf Ki = 1 nmol/L and C-Raf Ki = 0.3 nmol/L).

Carnahan et al. found that in cells with wild-type B-Raf and mutant K-ras, exposure to Raf inhibitors resulted in a dose-dependent and sustained paradoxical activation of mitogen-activated protein kinase (MAPK) signaling. Inhibition of BRaf resulted in cell cycle entry and increased proliferation.

In some embodiments, a method of treating, preventing, or alleviating radiation dermatitis is provided by administering to a subject in need thereof a topical composition comprising a therapeutically and/or prophylactically effective amount of at least one BRAF inhibitor or combination thereof and a pharmaceutically acceptable carrier or excipient.

At least one BRaf inhibitor used in the composition of the present invention belongs to several structural and functional groups A-D.

A. Commercially available BRaf inhibitors selected from BAY43-9006 (sorafenib), LGX818 (encorafenib), PLX4032 (vemurafenib), GSK2118436 (dabrafenib), ARQ736, ARQ680, AZ628, C-1, C-15, C-19, C-A , CEP-32496, GDC-0879, NMS-P186, NMS-P349, NMS-P383, NMS-P396, NMS-P730, PLX3603 (RO5212054), PLX4720 (difluorophenyl sulfonamine), PF-04880594, PLX4734, RAF265, RO49 87655 , SB590885, ZM336372, BMS908662, WYE-130600, TAK632, MLN 2480, XL281.

C-1, C-15, C-19, C-A, C-A and ZM336372 are disclosed, for example, in Carnahan et.al. (Mol. Cancer Ther. 2010 Aug;9(8):2399-410) and Smith et.al. (J. Med. Chem., 2009, 52 (20), pp 6189-619), and they provide the following molecular structures:

C-1 C-15 C-19 C-A ZM336372 (ZM)

B. BRaf inhibitors of formula (I):

wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1- dimethylethyl)-1-methyl-1H-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof;

C. BRaf inhibitors of formula (II):

wherein R is NHR1, wherein R1 is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or solvate thereof;

D. BRaf inhibitors of formula (III):

wherein R is NHR1, wherein R1 is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof;

or a combination thereof; and a pharmaceutically acceptable carrier or excipient.

An exceptional BRaf inhibitor is a compound of formula (I), wherein R is 3-(trifluoromethoxy)phenyl.

The compounds of formulas (I), (II) and (III) are disclosed in international publication No. WO2019/026065, Shelach N.

In some embodiments, the compounds of the present disclosure provide increased cell proliferation.

Compositions

In some embodiments, provided herein is a pharmaceutical composition comprising at least one BRAF inhibitor of Groups A-D described above.

According to some other embodiments, the above pharmaceutical composition may contain from about 0.1% wt./mass. to approximately 1% w/w at least one BRAF inhibitor from groups A-D or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof, based on the total weight of the composition. For example, the pharmaceutical composition may contain approximately 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9 % or 1% w/w, including values and ranges therebetween, of the total weight of the composition, of at least one of the BRaf inhibitors of Groups A-D disclosed herein.

In some embodiments, the pharmaceutical composition may contain from about 0.1% to about 0.2%, from about 0.1% to about 0.3%, from about 0.1% to about 0.4%, from about 0 .1% to about 0.5%, from about 0.1% to about 0.6%, from about 0.1% to about 0.7%, from about 0.1% to about 0.8%, from from about 0.2% to about 0.9%, from about 0.2% to about 1%, from about 0.25% to about 0.5%, from about 0.25% to about 0.7%, from about 0.25% to about 0.8%, about 0.5% to about 0.75%, or about 0.5% to about 1% w/w, including values and ranges therebetween, based on per total weight of the composition, any of the BRaf inhibitors disclosed herein.

According to some other embodiments, the above pharmaceutical composition may contain from about 1% wt./mass. up to approximately 5% w/w at least one BRAF inhibitor of groups A-D or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof, based on the total weight of the composition. For example, the pharmaceutical composition may contain approximately 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4, 9% or 5% w/w, including values and ranges therebetween, of any of the BRaf inhibitors of Groups A-D disclosed herein.

In some embodiments, the pharmaceutical composition may contain from about 1% to about 3%, from about 1% to about 4%, from about 1.5% to about 5%, from about 1.5% to about 4.5%, from about 1.5% to about 3.5%, from about 1.5% to about 3%, from about 2% to about 5%, from about 2% to about 4.5%, from about 2% to about 4 %, from about 2.5% to about 5%, from about 2.5% to about 4.5%, from about 2.5% to about 4%, from about 3% to about 5%, from about 3, 5% to about 5% w/w, including values and ranges therebetween, based on the total weight of the composition, of any of the BRaf inhibitors disclosed herein.

According to some other embodiments, the pharmaceutical composition may contain from about 5% wt./mass. up to approximately 10% w/w a BRAF inhibitor of groups A-D or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof, based on the total weight of the composition. For example, the pharmaceutical composition may contain approximately 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6, 9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9% , 8%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9 %, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9% or 10% wt. ./wt., including values and ranges between those indicated, of any of the BRaf inhibitors disclosed herein of groups A-D.

In some other embodiments, the pharmaceutical composition may contain from about 5% to about 9%, from about 5% to about 8.5%, from about 5% to about 8%, from about 5% to about 7.5%, from about 5% to about 7%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8.5%, about 6% to about 8%, about 7% to about 10%, from about 7% to about 9.5%, from about 7% to about 8.5%, from about 7.5% to about 10%, from about 8% to about 10% w/w ., including values and ranges between those indicated, based on the total weight of the composition, of any of the BRaf inhibitors disclosed herein.

In some other embodiments, the pharmaceutical composition may contain from about 1% to about 10%, from about 1% to about 8%, from about 1% to about 7%, from about 2% to about 8%, from about 2% to about 7%, about 2% to about 6%, about 2.5% to about 7.5%, about 2.5% to about 5.5%, about 3% to about 8%, about 3% to about 7%, from about 4% to about 8%, from about 4% to about 7%, from about 4.5% to about 7.5%, from about 4.5% to about 7%, or from about 4.5% to about 6.5% w/w, including values and ranges therebetween, based on the total weight of the composition, of any of the BRaf inhibitors disclosed herein.

In some embodiments, a pharmaceutical composition containing any of the compounds disclosed herein is formulated for external use. External application involves local application of the composition to an area of skin of a subject who is suffering from radiation dermatitis or will be undergoing radiation therapy.

In some embodiments, provided herein is a pharmaceutical composition for topical use comprising at least one Group A-D BRAF inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof, and a pharmaceutically acceptable carrier or excipient. Compositions intended for external use (topical compositions) may be in the form of a gel, hydrogel, ointment, cream, paste, foam, spray, lotion, liquid preparation or skin patch and may contain any of the disclosed compounds in any described herein document quantities.

In some embodiments, the topical pharmaceutical composition comprises a BRAF inhibitor (codenamed LUT014) of the formula:

in any of the amounts disclosed herein and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein is a pharmaceutical composition for external use comprising LUT014 in any of the w/w% amounts disclosed herein and a pharmaceutically acceptable carrier or excipient. The topical composition containing LUT014 can be formulated as a dosage form selected from ointment, cream, paste, gel, hydrogel, foam, spray, lotion, liquid preparation and skin patch.

Another dosage form for external use may be a paste. Pastes are thick, semi-solid dosage forms for external use containing a high proportion of finely divided solids such as starch, zinc oxide, calcium carbonate and talc. Another component of pastes is a base, which may be a hydrocarbon, an absorbent ingredient, a water-miscible ingredient, or a water-soluble ingredient. Pastes are less greasy than ointments.

Compositions for external use useful in the present disclosure may be formulated as a solution. Such compositions may contain an emollient, preferably from about 1% to about 50% emollient(s). As used herein, the term "emollient" refers to substances used to prevent or reduce dryness and to protect the skin. A variety of suitable emollients are known and may be used in the present disclosure. For example, Sagarin, Cosmetics, Science and Technology, 2nd edition, volume 1, pp. 32-43 (1972) and International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626 and 1654-55 (The Cosmetic, Toiletry, and Fragrance Assoc., Washington, D.C., 7th edition, 1997) (“ICI Handbook”) contain many examples of suitable substances.

A lotion can be obtained from such a solution. Lotions typically contain from about 1% to about 20% (for example, from about 5% to about 10%) emollient(s) and from about 50% to about 90% (for example, from about 60% up to approximately 80%) water.

Another type of product that can be formulated from a solution is a cream. The cream typically contains from about 5% to about 50% (for example, from about 10% to about 20%) emollient(s) and from about 45% to about 85% (for example, from about 50% up to approximately 75%) water.

Another type of product that can be formulated from a solution is an ointment. The ointment may contain a simple base in the form of animal fats or vegetable oils or semi-solid hydrocarbons. The ointment may contain from about 2% to about 10% emollient(s) plus from about 0.1% to about 2% thickener(s). A more complete description of thickeners or thickening agents useful herein can be found in Sagarin, Cosmetics, Science and Technology, 2nd edition, volume 1, pp. 72-73 (1972) and ICI Handbook pp. 1693-1697.

Compositions for external use useful in the present disclosure may be formulated as emulsions. If the carrier in the topical composition is an emulsion, from about 1% to about 10% (eg, from about 2% to about 5%) of the carrier is(are) emulsifier(s). Emulsifiers can be nonionic, anionic or cationic. Suitable emulsifiers are disclosed, for example, in McCutcheon's Detergents and Emulsifiers, North American Edition, pp. 317-324 (1986) and ICI Handbook, pp. 1673-1686.

Lotions and creams can be formulated as emulsions. Such lotions and creams may contain from 0.5% to about 5% emulsifier(s). The creams may contain from about 1% to about 20% (eg, from about 5% to about 10%) emollient(s); from about 20% to about 80% (for example, from 30% to about 70%) water; and from about 1% to about 10% (for example, from about 2% to about 5%) emulsifier(s).

The topical compositions of the present disclosure may also be formulated as a gel (eg, an aqueous, alcoholic, alcoholic/aqueous or oily gel) using suitable gelling agent(s). Suitable gelling agents for aqueous gels include, but are not limited to, natural gums, polymers and copolymers of acrylic acid and acrylates, and cellulose derivatives (eg, hydroxymethylcellulose and hydroxypropylcellulose). Suitable oil gelling agents include, but are not limited to, hydrogenated butylene-ethylene-styrene copolymer and hydrogenated ethylene-propylene-styrene copolymer. Gel compositions may contain from about 0.1% to 5%, by weight, of such gelling agents.

In addition to the above-mentioned carriers and excipients, other emollients and surfactants may be included in topical compositions, including triolein, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1) monostearate, glyceryl monooleate, sucrose distearate, polyethylene glycol (50 ) monostearate, octylphenoxypoly(ethyleneoxy)ethanol, decaglycerol pentaisostearate, sorbitan sesquioleate, hydroxylated lanolin, lanolin, triglyceryl diisostearate, polyoxyethylene (2) oleyl ether, calcium stearoyl-2-lactylate, methyl glucoside sesquistearate, sorbitan monopalmitate, methoxy copolymer polyethylene glycol-22/dodecyl glycol (Elfacos E200), polyethylene glycol-45/dodecyl glycol copolymer (Elfacos ST9), polyethylene glycol 400 distearate and sterol-containing extracts of lanolin, glycol stearate and glyceryl stearate; alcohols such as cetyl alcohol and lanolin alcohol; myristates such as isopropyl myristate; cetyl palmitate; cholesterol; stearic acid; propylene glycol; glycerin, sorbitol, etc.

Methods

Disclosed herein are methods for treating, preventing, and/or reducing the side effects of radiation therapy known as radiation dermatitis.

In some embodiments, radiation dermatitis is a dermatologic adverse reaction or skin adverse reaction induced by radiation therapy.

In some embodiments, provided herein is a method of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one Group A-D BRAF inhibitor and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein are methods of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one group A BRaf inhibitor and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein are methods of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one group B BRaf inhibitor and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein are methods of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one group B BRaf inhibitor ( formula (I), wherein R represents 3-(trifluoromethoxy)phenyl, code name LUT014) in any of the w/w% amounts disclosed herein and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein are methods of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one group C BRaf inhibitor and a pharmaceutically acceptable carrier or excipient.

In some embodiments, provided herein are methods of treating, ameliorating, and/or preventing radiation dermatitis caused by radiotherapy in a subject in need thereof, comprising administering a therapeutically and/or prophylactically effective amount of a composition comprising at least one group D BRaf inhibitor and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the subject is a mammal, such as a human, a dog, and/or a cat.

In some embodiments, the methods disclosed herein provide for the external administration of a therapeutically and/or prophylactically effective amount of the compounds/compositions of the present disclosure.

In some embodiments, the methods disclosed herein provide topical administration of from about 0.1 mg/day to about 1 mg/day of one or more compounds of the present disclosure. In some embodiments, the methods disclosed herein include topical administration of about 0.1 mg/day, about 0.2 mg/day, about 0.3 mg/day, about 0.4 mg/day, about 0.5 mg/day. day, approximately 0.6 mg/day, approximately 0.7 mg/day, approximately 0.8 mg/day, approximately 0.9 mg/day, or approximately 1 mg/day, including values and ranges between those indicated, one or more compounds of the present disclosure. In some embodiments, the methods disclosed herein include topical administration of about 0.1 mg/day to about 0.5 mg/day, about 0.2 mg/day to about 0.8 mg/day, about 0. 2 mg/day to about 0.5 mg/day, or from about 0.5 mg/day to about 1 mg/day, including values and ranges therebetween, of one or more compounds of the present disclosure.

In some embodiments, the methods disclosed herein provide topical administration of from about 1 mg/day to about 5 mg/day of one or more compounds of the present disclosure. In some embodiments, the methods disclosed herein include topical administration of approximately 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day, including values and ranges therebetween, of one or more compounds of the present disclosure.

In some embodiments, the methods disclosed herein provide topical administration of from about 5 mg/day to about 10 mg/day of one or more compounds of the present disclosure. In some embodiments, the methods disclosed herein include topical administration of about 5 mg/day, about 5.5 mg/day, about 6 mg/day, about 6.5 mg/day, about 7 mg/day, about 7.5 mg/day, approximately 8 mg/day, approximately 8.5 mg/day, approximately 9 mg/day, approximately 9.5 mg/day, or approximately 10 mg/day, including values and ranges therebetween, of one or more compounds of this disclosure.

In some embodiments, the methods disclosed herein include topical administration of about 1 mg/day to about 10 mg/day, about 1 mg/day to about 8 mg/day, about 2 mg/day to about 8 mg/day , from about 2.5 mg/day to about 7.5 mg/day, from about 3 mg/day to about 8 mg/day, from about 3 mg/day to about 6 mg/day, or from about 4 mg/day up to approximately 8 mg/day, including values and ranges therebetween, of one or more compounds of the present disclosure.

In some embodiments, the amount of compound used depends on the nature of the compound, the route of application, and/or the severity of the skin reaction. The prophylactically and/or therapeutically effective amount to be administered to a patient may be determined through optimal dose-finding clinical studies known in the art.

In some embodiments, the methods disclosed herein provide a reduction in the severity of reactions constituting radiation dermatitis.

The most commonly used systems for grading the severity of skin adverse events are the Radiation Therapy Oncology Group (RTOG) grading scale and the National Cancer Institute's Common Terminology Criteria for Adverse Events. , CTCAE) version 5.0, which define the 6 degrees shown below.

Radiation dermatitis: (reproduced from page 72 of CTCEA version 5):

Level 0 - no change

Grade 1 - mild erythema or dry desquamation

Grade 2 - moderate to intense erythema; focal wet desquamation; mainly limited to skin folds and flexure areas; moderate swelling.

Grade 3 - wet desquamation in areas other than skin folds and flexures; bleeding induced by the slightest trauma or friction.

Degree 4 - life-threatening manifestations; skin necrosis or ulceration of the entire thickness of the dermis; spontaneous bleeding from the affected site; skin grafting is indicated.

Level 5 - fatal

RTOG grading scale for radiation dermatitis:

Level 0 - no change

Grade 1 - mild erythema; dry desquamation; hair loss; decreased sweating

Grade 2 - painful or bright erythema; moderate swelling; focal wet desquamation

Grade 3 - wet desquamation in areas other than skin folds; pastiness

Grade 4 - ulceration; bleeding; necrosis

Level 5 - fatal

In some embodiments, methods disclosed herein provide a reduction in the severity of skin adverse reactions from grade 4 to grade 3, 2, 1, or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or according to the Radiotherapy Oncology Study Group (RTOG) grading scale.

In some embodiments, methods disclosed herein provide a reduction in the severity of skin adverse reactions from grade 3 to grade 2, 1, or 0, as defined by NCI-CTCAE version 5.0 or the Radiation Therapy Oncology Study Group (RTOG) grading scale ).

In some embodiments, the methods disclosed herein provide a reduction in the severity of skin adverse reactions from grade 2 to grade 1 or 0, as defined by NCI-CTCAE version 5.0 or according to the Radiation Therapy Oncology Study Group (RTOG) grading scale.

In some embodiments, the methods disclosed herein provide a reduction in the severity of skin adverse reactions from grade 1 to grade 0, as defined by NCI-CTCAE version 5.0 or according to the Radiation Therapy Oncology Study Group (RTOG) grading scale.

In some embodiments, the methods disclosed herein provide prevention, partially or completely, of the development of adverse skin reactions.

In some embodiments, the methods disclosed herein provide prevention, in part or in whole, of grade 4, grade 3, grade 2, or grade 1 skin adverse reactions, as defined by NCI-CTCAE version 5.0 or according to the NCI-CTCAE grading scale. study of radiotherapy in oncology (RTOG).

In some embodiments, the methods disclosed herein prevent the worsening of an adverse skin reaction. For example, in some embodiments, the methods disclosed herein provide prevention of worsening of a grade 0 to grade 1, 2, 3, or 4 cutaneous adverse reaction, as defined by NCI-CTCAE version 5.0 or according to the Radiotherapy Study Group grading scale in Oncology (RTOG).

In another embodiment, methods disclosed herein provide prevention of worsening grade 1 to grade 2, 3, or 4 cutaneous adverse reactions, as defined by NCI-CTCAE version 5.0 or the Radiation Therapy Oncology Study Group (RTOG) grading scale. ).

In another embodiment, the methods disclosed herein provide prevention of worsening of a grade 2 to grade 3 or 4 cutaneous adverse reaction, as defined by NCI-CTCAE version 5.0 or according to the Radiation Therapy Oncology Study Group (RTOG) grading scale.

In another embodiment, the methods disclosed herein provide prevention of worsening of a grade 3 to grade 4 cutaneous adverse reaction as defined by NCI-CTCAE version 5.0 or the Radiation Therapy Oncology Study Group (RTOG) grading scale.

In some embodiments, the use of a topical composition comprising a therapeutically and/or prophylactically effective dose of at least one BRaf inhibitor or combination thereof and a pharmaceutically acceptable carrier or excipient is provided for the treatment, prevention or relief of radiation dermatitis by topical application to a person in need of this subject.

In some embodiments, the above-mentioned use is provided, wherein said composition comprises a therapeutically and/or prophylactically effective dose of at least one BRaf inhibitor selected from BAY43-9006 (sorafenib), LGX818 (encorafenib), PLX4032 (vemurafenib), GSK2118436 (dabrafenib) , ARQ736, ARQ680, AZ628, C-1, C-15, C-19, C-A, CEP-32496, GDC-0879, NMS-P186, NMS-P349, NMS-P383, NMS-P396, NMS-P730, PLX3603 (RO5212054), PLX4720 (дифторфенил-сульфонамина), PF-04880594, PLX4734, RAF265, RO4987655, SB590885, ZM336372, BMS908662, WYE-130600, TAK632, MLN 2480, XL281,

compounds of formula (I):

wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1- dimethylethyl)-1-methyl-1H-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof;

compounds of formula (II):

wherein R is NHR1, wherein R1 is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or solvate thereof;

compounds of formula (III):

wherein R is NHR1, wherein R1 is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof;

or combinations thereof; and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the above use is provided wherein the BRaf inhibitor is a compound of formula (I) and wherein R is 3-(trifluoromethoxy)phenyl. In some embodiments, a use according to any of the above embodiments is provided, wherein the BRAF inhibitor inhibits BRaf activity and provides increased cell proliferation.

In some embodiments, the use of a topical composition of the present disclosure is provided, comprising a therapeutically and/or prophylactically effective dose of at least one BRAF inhibitor or combination thereof and a pharmaceutically acceptable carrier or excipient, for treating, preventing, or alleviating radiation dermatitis by topical application. in a subject in need thereof, said composition being formulated for external use.

In some embodiments, the above-mentioned use is provided, wherein the topical composition is in the form of a gel, hydrogel, ointment, cream, paste, foam, spray, lotion, liquid preparation, or skin patch.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the BRaf inhibitor in the composition is present at a concentration of 1% w/w. up to 5% w/w from the total mass of the composition.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the BRaf inhibitor in the composition is present at a concentration of from 0.1% w/w. up to 10% w/w from the total mass of the composition.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides a reduction in the severity or prevention of worsening of radiation dermatitis.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides a reduction in the severity of an adverse skin reaction from grade 4 to grade 3, 2, 1, or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE) version 5.0 or according to the Radiotherapy Oncology Study Group (RTOG) grading scale.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides a reduction in the severity of an adverse skin reaction from grade 3 to grade 2, 1, or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding degrees according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides a reduction in the severity of an adverse skin reaction from grade 2 to grade 1 or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding degrees according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides a reduction in the severity of an adverse skin reaction from grade 1 to grade 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or equivalent degrees according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides prevention of worsening of a grade 0 to grade 1, 2, 3, or 4 skin adverse reaction, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE) version 5.0 or equivalent grades according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides prevention of worsening of a grade 1 to grade 2, 3, or 4 cutaneous adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding degrees according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides prevention of worsening of a grade 2 to grade 3 or 4 cutaneous adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding degrees according to RTOG.

In some embodiments, use of any of the compositions of the present disclosure is provided, wherein the use provides prevention of worsening of a grade 3 to grade 4 cutaneous adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or equivalent degrees according to RTOG.

Examples

Example 1.

Effect of compounds - LUT012, LUT013, LUT014, LUT015, LUT016, LUT017, LUT-019, LUT020, C-1 and vemurafenib - on the proliferation of MIA PaCa cells.

In this example, the effect of the compounds on the proliferation of MIA PaCa2 K-ras cells was examined. Compounds that induce ERK phosphorylation were expected to also induce proliferation of Mia PaCa cells.

Cells were seeded in starvation medium at a concentration of 5000 cells/well in a 96-well plate for 24 hours at 37°C, 5% CO ₂ . Test compounds were added at different concentrations ranging from 0.002 pM to 10 pM. Controls consisted of untreated cells and 0.1% DMSO vehicle. Cells were incubated at 37°C, 5% CO2, for 72 hours and then tested for proliferation using an ATPlite proliferation assay kit (Perkin-Elmer). Each result represents the average of 6 holes. Results are presented as percentage of proliferation above background compared to DMSO control.

The result for the concentration of compounds that provided the greatest proliferation was compared with that of DMSO. DMSO was taken as 100%. After 72 hours, % proliferation compared to that of DMSO control induced by C-1 was 30%, 173% for LUT013, 116% for LUT014, 29% for LUT015, 110% for LUT016, 174% for LUT017 , 20% for LUT012, 7% for LUT019 and 12% for LUT020. Vemurafenib showed 12% proliferation compared to DMSO (see Figures 1-6).

Claims (28)

1. The use of a composition for external use containing a therapeutically and/or prophylactically effective dose of at least one BRaf inhibitor or a combination thereof and a pharmaceutically acceptable carrier or excipient for the treatment, prevention or relief of radiation dermatitis by external application to a subject in need thereof, wherein said at least one BRaf inhibitor is selected from: BAY43-9006 (sorafenib), LGX818 (encorafenib), PLX4032 (vemurafenib), GSK2118436 (dabrafenib), ARQ736, ARQ680, AZ628, C-1, C-15, C-19 , C-A, CEP-32496, GDC-0879, NMS-P186, NMS-P349, NMS-P383, NMS-P396, NMS-P730, PLX3603 (RO5212054), PLX4720 (difluorophenyl sulfonamine), PF-04880594, PLX4734, RAF265 , RO4987655, SB590885, ZM336372, BMS908662, WYE-130600, TAK632, MLN 2480, XL281, compounds of formula (I): (I), wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1- dimethylethyl)-1-methyl-1H-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof; compounds of formula (II): (II), wherein R is NHR1, wherein R1 is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or solvate thereof; compounds of formula (III): (III), wherein R is NHR1, wherein R1 is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or solvate thereof. 2. Use according to claim 1, wherein the BRaf inhibitor is a compound of formula (I), and wherein R is 3-(trifluoromethoxy)phenyl. 3. Application according to any one of paragraphs. 1, 2, in which a BRaf inhibitor inhibits BRaf activity and provides increased cell proliferation. 4. Use according to claim 1, wherein said composition is formulated for external use. 5. Use according to claim 4, wherein the composition is in the form of a gel, hydrogel, ointment, cream, paste, foam, spray, lotion, liquid preparation or skin patch. 6. Application according to any one of paragraphs. 1-5, in which the BRaf inhibitor in the composition is present in a concentration of 1% wt./mass. up to 5% w/w from the total mass of the composition. 7. Application according to any one of paragraphs. 1-5, in which the BRaf inhibitor in the composition is present in a concentration of 0.1% wt./mass. up to 10% w/w from the total mass of the composition. 8. Application according to any one of paragraphs. 1-7, where the use reduces the severity or prevents the worsening of radiation dermatitis. 9. The use of claim 8, wherein the use provides a reduction in the severity of the cutaneous adverse reaction from grade 4 to grade 3, 2, 1, or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or according to the Radiotherapy Oncology Study Group (RTOG) grading scale. 10. The use of claim 8, wherein the use provides a reduction in the severity of the cutaneous adverse reaction from grade 3 to grade 2, 1, or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding grades. according to RTOG. 11. The use of claim 8, wherein the use provides a reduction in the severity of the skin adverse reaction from grade 2 to grade 1 or 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades. . 12. The use of claim 8, wherein the use provides a reduction in the severity of the skin adverse reaction from grade 1 to grade 0, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades. 13. The use of claim 8, wherein the use provides prevention of worsening of a grade 0 to grade 1, 2, 3, or 4 cutaneous adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding degrees according to RTOG. 14. The use of claim 8, wherein the use provides prevention of worsening of a cutaneous adverse reaction of grade 1 to grade 2, 3, or 4, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding grades. according to RTOG. 15. The use of claim 8, wherein the use provides prevention of worsening of a grade 2 to grade 3 or 4 cutaneous adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades. . 16. The use of claim 8, wherein the use provides prevention of worsening of a grade 3 to grade 4 skin adverse reaction, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or corresponding RTOG grades.